Culture

In 2005, an ultramarathon runner ran continuously 560 kilometers (350 miles) in 80 hours, without sleeping or stopping. This distance was roughly 324,000 times the runner's body length. Yet this extreme feat pales in comparison to the relative distances that fruit flies can travel in a single flight, according to new research from Caltech.

Caltech scientists have now discovered that fruit flies can fly up to 15 kilometers (about 9 miles) in a single journey--6 million times their body length, or the equivalent of over 10,000 kilometers for the average human. In comparison to body length, this is further than many migratory species of birds can fly in a day. To discover this, the team conducted experiments in a dry lakebed in California's Mojave Desert, releasing flies and luring them into traps containing fermenting juice in order to determine their top speeds.

The research was conducted in the laboratory of Michael Dickinson, Esther M. and Abe M. Zarem Professor of Bioengineering and Aeronautics and executive officer for biology and biological engineering. A paper describing the study appears in the journal Proceedings of the National Academy of Sciences on April 20.

The work was motivated by a longstanding paradox that was identified in the 1940s by Theodosius Dobzhansky and other pioneers of population genetics who studied Drosophila species across the Southwest United States. Dobzhansky and others found that fly populations separated by thousands of kilometers appeared much more genetically similar than could be easily explained by their estimates of how far the tiny flies could actually travel. Indeed, when biologists would release flies outdoors, the insects would often simply buzz around in circles over short distances, like they do in our kitchens.

Did flies behave differently when out in the wild, in search of food? In the 1970s and '80s, a group of population geneticists attempted to address this paradox by coating hundreds of thousands of flies in fluorescent powder and releasing them one evening in Death Valley. Remarkably, the group detected a few fluorescent flies in buckets of rotting bananas up to 15 kilometers away the next day.

"These simple experiments raised so many questions," says Dickinson. "How long did it take them to fly there? Were they just blown by the wind? Was it an accident? I have read that paper many times and found it very inspiring. No one had tried to repeat the experiment in a way that would make it possible to measure whether the flies were carried by the wind, how fast they were flying, and how far they can really go."

To measure how flies disperse and interact with the wind, the team designed "release and recapture" experiments. Led by former postdoctoral scholar Kate Leitch, the team made several trips to Coyote Lake, a dry lakebed 140 miles from Caltech in the Mojave Desert, with hundreds of thousands of the common lab fruit fly, Drosophila melanogaster, in tow.

The aim was to release the flies, lure them into traps at set locations, and measure how long it took the insects to fly there. To do this, the team set up 10 "odor traps" in a circular ring, each located along a one-kilometer radius around the release site. Each trap contained a tantalizing cocktail of fermenting apple juice and champagne yeast, a combination that produces carbon dioxide and ethanol, which are irresistible to a fruit fly. The traps also each had a camera, and were constructed with one-way valves so that the flies could crawl into the trap toward the cocktail but not back out. In addition, the researchers set up a weather station to measure the wind speed and direction at the release site throughout each experiment; this would indicate how the flies' flight was affected by the wind.

So as not to interfere with their flight performance, the team did not coat the flies with identifiers like fluorescent powder. So how did they know they were catching their own fruit flies? Before the release, the team first placed the traps and checked them over time, and found that although D. melanogaster are found at date farms within the Mojave, they are extremely rare at Coyote Lake.

The flies released by the team had been originally collected at a fruit stand and then were raised in the lab, but they were not genetically modified in any way. The team performed the experiments after receiving permits from the Bureau of Land Management.

At experiment time, the team drove the buckets of flies to the center of the circle of traps. The buckets contained plenty of sugar, so that the insects would be fully energized for their flight; however, they contained no protein, giving the flies a strong drive to search for protein-rich food. The team estimated that the flies would not be able to smell the traps from the center of the ring, forcing them to disperse and search.

At a precise time, a team member at the center of the circle opened up the buckets simultaneously and quickly released the flies.

"The person who stayed at the center of the ring to open the lids off of all the buckets witnessed quite a spectacle," says Leitch. "It was beautiful. There were so many flies--so many that you were overwhelmed by the whirring drone. A few of them would land on you, often crawling in your mouth, ears, and nose."

The team repeated these experiments under various wind conditions.

It took about 16 minutes for the first fruit flies to cover one kilometer to reach the traps, corresponding to a speed of approximately 1 meter per second. The team interpreted this speed as a lower limit (perhaps these first flies had buzzed around in circles a bit after release or did not fly in a perfectly straight line). Previous studies from the lab showed that a fully fed fruit fly has the energy to fly continuously for up to three hours; extrapolating, the team concluded that D. melanogaster can fly roughly 12 to 15 kilometers in a single flight, even into a gentle breeze, and will go further if aided by a tailwind. This distance is approximately 6 million times the average body length of a fruit fly (2.5 millimeters, or one tenth of an inch). As an analogy, this would be like the average human covering just over 10,000 kilometers in a single journey--roughly the distance from the North Pole to the equator.

"The dispersal capability of these little fruit flies has been vastly underestimated. They can travel as far or farther than most migratory birds in a single flight. These flies are the standard laboratory model organism, but they are almost never studied outside of the laboratory and so we had little idea what their flight capabilities were," Dickinson says.

In 2018, the Dickinson laboratory discovered that fruit flies use the sun as a landmark in order to fly in a straight line in search of food; flying aimlessly in circles could be deadly, so there is an evolutionary benefit to being able to navigate efficiently. After completing the release experiments described in this study, the team proposed a model that suggests that each fly chooses a direction at random, uses the sun to fly straight in that direction, and carefully regulates its forward speed while allowing itself to be blown sideways by the wind. This enables it to cover as much distance as possible and increases the probability that it will encounter a plume of odor from a food source. The team compared their model with traditional models of random insect dispersal and found that their model could explain the results of the desert releases more accurately because of the flies' propensity to maintain a constant heading once released.

Even though D. melanogaster has been co-evolving with humans, this work shows that the fly brain still contains ancient behavioral modules. Dickinson explains: "For any animal, if you find yourself in the middle of nowhere and there's no food, what do you do? Do you just hop around and hope you find some fruit? Or do you say--'Okay, I'm going to pick a direction and go as far as I can in that direction and hope for the best.' These experiments suggest that that's what the flies do."

The research has broader implications for the field of movement ecology, which studies how populations move around the world, essentially shifting biomass for other animals to eat. In fact, during their early pre-release experiments to check for local populations of Drosophila, the team several times caught an invasive species of fly, the spotted-wing Drosophila (Drosophila suzukii), which causes significant agricultural damage across the West Coast.

"We set up these traps in the middle of nowhere, not the Central Valley where there would be fields of food, and still we find these agricultural pests cruising through," says Dickinson. "It's kind of scary to see how far these introduced species can travel using simple navigational strategies."

Using the Atacama Large Millimeter/submillimeter Array (ALMA), astronomers found a rotating baby galaxy 1/100th the size of the Milky Way at a time when the Universe was only seven percent of its present age. Thanks to assistance by the gravitational lens effect, the team was able to explore for the first time the nature of small and dark "normal galaxies" in the early Universe, representative of the main population of the first galaxies, which greatly advances our understanding of the initial phase of galaxy evolution.

"Many of the galaxies that existed in the early Universe were so small that their brightness is well below the limit of the current largest telescopes on Earth and in Space, making difficult to study their properties and internal structure," says Nicolas Laporte, a Kavli Senior Fellow at the University of Cambridge. "However, the light coming from the galaxy named RXCJ0600-z6, was highly magnified by gravitational lensing, making it an ideal target for studying the properties and structure of a typical baby galaxies."

Gravitational lensing is a natural phenomenon in which light emitted from a distant object is bent by the gravity of a massive body such as a galaxy or a galaxy cluster located in the foreground. The name "gravitational lensing" is derived from the fact that the gravity of the massive object acts like a lens. When we look through a gravitational lens, the light of distant objects is intensified and their shapes are stretched. In other words, it is a "natural telescope" floating in space.

The ALMA Lensing Cluster Survey (ALCS) team used ALMA to search for a large number of galaxies in the early Universe that are enlarged by gravitational lensing. Combining the power of ALMA, with the help of the natural telescopes, the researchers are able to uncover and study fainter galaxies.

Why is it crucial to explore the faintest galaxies in the early Universe? Theory and simulations predict that the majority of galaxies formed few hundred millions years after the Big-Bang are small, and thus faint. Although several galaxies in the early Universe have been previously observed, those studied were limited to the most massive objects, and therefore the less representative galaxies, in the early Universe, because of telescopes capabilities. The only way to understand the standard formation of the first galaxies, and obtain a complete picture of galaxy formation, is to focus on the fainter and more numerous galaxies.

The ALCS team performed a large-scale observation program that took 95 hours, which is a very long time for ALMA observations, to observe the central regions of 33 galaxy clusters that could cause gravitational lensing. One of these clusters, called RXCJ0600-2007, is located in the direction of the constellation of Lepus, and has a mass 1000 trillion times that of the Sun. The team discovered a single distant galaxy that is being affected by the gravitational lens created by this natural telescope. ALMA detected the light from carbon ions and stardust in the galaxy and, together with data taken with the Gemini telescope, determined that the galaxy is seen as it was about 900 million years after the Big Bang (12.9 billion years ago). Further analysis of these data suggested that a part of this source is seen 160 times brighter than it is intrinsically.

By precisely measuring the mass distribution of the cluster of galaxies, it is possible to "undo" the gravitational lensing effect and restore the original appearance of the magnified object. By combining data from Hubble Space Telescope and the European Southern Observatory's Very Large Telescope with a theoretical model, the team succeeded in reconstructing the actual shape of the distant galaxy RXCJ0600-z6. The total mass of this galaxy is about 2 to 3 billion times that of the Sun, which is about 1/100th of the size of our own Milky Way Galaxy.

What astonished the team is that RXCJ0600-z6 is rotating. Traditionally, gas in the young galaxies was thought to have random, chaotic motion. Only recently has ALMA discovered several rotating young galaxies that have challenged the traditional theoretical framework, but these were several orders of magnitude brighter (larger) than RXCJ0600-z6.

"Our study demonstrates, for the first time, that we can directly measure the internal motion of such faint (less massive) galaxies in the early Universe and compare it with the theoretical predictions", says Kotaro Kohno, a professor at the University of Tokyo and the leader of the ALCS team.

"The fact that RXCJ0600-z6 has a very high magnification factor also raises expectations for future research," explains Seiji Fujimoto, a DAWN fellow at the Niels Bohr Institute. "This galaxy has been selected, among hundreds, to be observed by the James Webb Space Telescope (JWST), the next generation space telescope to be launched this autumn. Through joint observations using ALMA and JWST, we will unveil the properties of gas and stars in a baby galaxy and its internal motions. When the Thirty Meter Telescope and the Extremely Large Telescope are completed, they may be able to detect clusters of stars in the galaxy, and possibly even resolve individual stars. There is an example of gravitational lensing that has been used to observe a single star 9.5 billion light-years away, and this research has the potential to extend this to less than a billion years after the birth of the Universe."

These observation results were presented in Seiji Fujimoto et al. "ALMA Lensing Cluster Survey: Bright [CII] 158 μm Lines from a Multiply Imaged Sub-L* Galaxy at z = 6.0719" in the Astrophysical Journal on April 22, 2021, and Nicolas Laporte et al. "ALMA Lensing Cluster Survey: a strongly lensed multiply imaged dusty system at z > 6" in the Monthly Notices of the Royal Astronomical Society on April 22, 2021.

When it comes to friendships and rivalries, male dolphins know who the good team players are. New findings, published in Nature Communications by University of Bristol researchers, reveal that male dolphins form a social concept of team membership based on cooperative investment in the team.

The Bristol researchers, with colleagues from the University of Zurich and University of Massachusetts, used 30 years of observational data from a dolphin population in Shark Bay, Western Australia, and sound playback experiments to assess how male dolphins responded to the calls of other males from their alliance network.

Dr Stephanie King, Senior Lecturer from Bristol's School of Biological Sciences who led the research, said: "Social animals can possess sophisticated ways of classifying relationships with members of the same species. In our own society, we use social knowledge to classify individuals into meaningful groups, like sports teams and political allies. Bottlenose dolphins form the most complex alliances outside humans, and we wanted to know how they classify these relationships."

Dr Simon Allen, Research Fellow at Bristol's School of Biological Sciences, who contributed to the study, added: "We flew drones above dolphin groups, recording their behaviour during the sound playbacks, tracking their movements underwater and revealing novel insights into how dolphins respond to the calls of other males in their network of allies."

Males responded strongly to all of the allies that had consistently helped them out in the past, even if they weren't currently close friends. On the other hand, they didn't respond strongly to males who hadn't consistently helped them out in the past, even if they were friends. What this shows is that these dolphins form social concepts of 'team membership', categorizing allies according to a shared cooperative history.

Dr King said: "Such concepts develop through experience and likely played a role in the cooperative behaviour of early humans. Our results show that cooperation-based concepts are not unique to humans, but also occur in other animal societies with extensive cooperation between non-kin."

The week of Thanksgiving last year, a postcard arrived in mailboxes in Christiansburg. A link to a survey was on the back. On the front, there was a picture that was, by then, very familiar to the residents of a town that made history in 2019 as the first place in the U.S. to have a residential drone delivery service: a yellow-winged drone with a small cardboard box tucked underneath it.

The survey's 20 questions were designed to measure how Christiansburg's 22,000 residents felt about drone delivery -- the first time that this question had ever been posed to a community that had actually experienced the service. The survey was developed and conducted by researchers from the Virginia Tech Mid-Atlantic Aviation Partnership (MAAP), a federally designated drone test site, and Lee Vinsel, an assistant professor of science, technology, and society in the College of Liberal Arts and Human Sciences.

The primary finding: 87 percent of people who responded to the survey reported that they liked the idea of drone delivery. The resoundingly positive results, published in the spring issue of Issues in Science and Technology, plant a new stake in the ground for the future of a technology still at the beginning of its transition from research to retail.

Interest in drone delivery is rising. The service in Christiansburg, run by Wing, Alphabet's drone-delivery subsidiary, is the most advanced of the handful of trial services operating today. But drone technology -- and the laws that regulate it -- are maturing, and it's expected that services like these could become routine in the next few years.

Whether they're successful or not will depend in large part on how the public responds. Delivering packages to homes unfolds in the public eye to a greater extent than many other applications for drones: People may see the drone in the commercial area where it picks up its cargo, at the customer's house, and in the neighborhoods in between.

Accurate estimates of public opinion are critical for the regulatory agencies developing rules that will govern its use and state and local governments considering whether to encourage it, in addition to the companies pioneering these services and hoping to scale their businesses.

Until now, though, data has been limited, and usually not encouraging: The handful of surveys on this topic have pegged public support for drone delivery at around 50 percent in the U.S. and lower in Europe and the U.K..

But several factors suggest that those anemic results might not be definitive.

First, crucially, these surveys polled people who had almost certainly never received a delivery by drone, and were speculating about a service they were imagining rather than reporting on one they'd experienced. Second, many of the survey questions frame their questions in a way that implies risk, asking respondents to rate their level of concern about potential problems selected by the researchers in advance. Highlighting potential negative outcomes may prompt a more negative overall sentiment.

Christiansburg, then, represented a unique research opportunity.

"Gauging people's reactions to new technologies can be really difficult, including because it's so easy to bias respondents' views," Vinsel said. "We wanted to create a survey that was as neutral as possible to examine sentiments about drone delivery. And Christiansburg was a great opportunity for us because it was a unique population that had actually experienced these systems."

The survey asked respondents about standard demographic factors and their typical response to new technologies. It asked about how familiar they were with drone delivery, how they'd found out about it, and what their general attitude toward it was. Instead of asking about specific risks and benefits, the researchers asked open-ended questions about what the respondents saw as positive and negative aspects of the technology.

The survey was approved by the Virginia Tech Institutional Review Board; Wing helped fund the survey development and distribution through an existing research contract with MAAP, but the analysis was funded entirely by Virginia Tech. Adeline Guthrie, a graduate student in the statistics in the College of Science and collaborator with the Statistical Applications and Innovations Group, assisted with data analysis.

The results were resoundingly positive.

Not only did 87 percent of respondents report positive sentiment about drone delivery, 89 percent indicated either that they were likely to use the service or already had, and 49 percent reported liking the idea of drones used for package delivery more than drones used for other purposes.

All of these results are dramatically different from those of other surveys, in which positive sentiment never exceeded 51 percent and delivery was a relatively unpopular application when ranked against others.

The survey also asked respondents if their opinion had changed since the pandemic. When COVID-19 hit Virginia in March, the number of people signing up for Wing's service and ordering drone deliveries spiked. Wing partnered with additional local businesses and worked with a school librarian to deliver books.

The survey results suggested that these contributions had helped. The pandemic popped up frequently in the open-ended question about positive aspects of the technology. Fifty-eight percent of Christiansburg survey respondents said that their opinion of drone delivery had improved -- a much bigger boost than was measured in a 2020 survey from the Consumer Technology Association that polled a general population sample.

Here again, Christiansburg residents' experience with drone delivery may have contributed to the jump -- seeing a favorite coffee shop find a new way to reach customers without in-person shopping or a neighbor's child receiving a delivery of sidewalk chalk and crackers, may resonate more than an abstract appreciation for contact-free delivery.

MAAP worked with Wing to launch the drone delivery program under the federal UAS Integration Pilot Program, a drone-integration initiative that brought together state agencies, local governments, and companies to advance the rollout of drone applications that could have significant benefits for communities (the trial is continuing under the IPP successor program BEYOND). MAAP and Wing conducted months of community outreach before the service launched, talking to thousands of Christiansburg residents about what the service would look like.

"One of the goals of the IPP was to take a community-oriented approach to drone integration," said Tombo Jones, MAAP's director. "There's not a shortcut here. You need careful, methodical research to demonstrate that the system is safe and reliable. Then you can take that information out into the community, and talk to people to learn what they're looking for and what their concerns are. It's rewarding to see how positive the results of this survey are, because they show that, when it's done the right way, developing new applications for drones can have a genuinely positive impact on a community."

The team is hoping that future research will reveal more detail about how people's opinions evolve before and after they're exposed to drone delivery, the aspects of drone delivery that inspire the greatest enthusiasm or strongest skepticism, and what factors help determine how someone will feel about the technology.

"The key thing is that speculation about technologies is different than actual experiences with them," Vinsel said. "Lots of factors influence how we feel about the technologies in our lives, but something scholars have found repeatedly over for the last 60 years is that familiarity breeds acceptance. To be at an early point in the rollout of this technology and be able to study a population that has actually experienced it is pretty exciting."

Diseases continue to be a major threat to coral reef health. For example, a relatively recent outbreak termed stony coral tissue loss disease is an apparently infectious waterborne disease known to affect at least 20 stony coral species. First discovered in 2014 in Miami-Dade County, the disease has since spread throughout the majority of the Florida's Coral Reef and into multiple countries and territories in the Caribbean. Some reefs of the northern section of Florida's Coral Reef are experiencing as much as a 60 percent loss of living coral tissue area.

A new study by researchers at Florida Atlantic University's Harbor Branch Oceanographic Institute reveals how a common antibiotic used to treat bacterial infections in humans is showing promise in treating disease-affected Montastraea cavernosa coral colonies in situ. M. cavernosa, also known as the Great Star Coral, is a hard or stony coral found widely throughout the tropical western Atlantic, including several regions currently affected by stony coral tissue loss disease. Preserving M. cavernosa colonies is of particular importance due to its high abundance and role as a dominant reef builder in the northern section of Florida's Coral Reef.

The objective of the study, published in Scientific Reports, was to experimentally assess the effectiveness of two intervention treatments: chlorinated epoxy and amoxicillin combined with Core Rx/Ocean Alchemists Base 2B as compared to untreated controls. Results showed that the Base 2B plus amoxicillin treatment had a 95 percent success rate at healing individual disease lesions. However, it did not necessarily prevent treated colonies from developing new lesions over time. Chlorinated epoxy treatments were not significantly different from untreated control colonies, suggesting that chlorinated epoxy treatments are an ineffective intervention technique for stony coral tissue loss disease.

"There are three possible scenarios that may explain the appearance of new lesions in the amoxicillin treated lesions of the corals that had healed in our study," said Erin N. Shilling, M.S., first author and a recent graduate of the Marine Science and Oceanography masters degree program at FAU Harbor Branch. "It's possible that the causative agent of stony coral tissue loss disease is still present in the environment and is re-infecting quiesced colonies. It also could be that the duration and dose of this antibiotic intervention was sufficient to arrest stony coral tissue loss disease at treated lesions, but insufficient at eliminating its pathogens from other areas of the coral colony."

The study was conducted approximately 2 kilometers offshore from Lauderdale-by-the-Sea in Broward County, Florida, at sites with a maximum depth of 10 meters. Both colony disease status and treated lesion status were analyzed independently so that the treatment's effectiveness at halting individual lesions could be assessed while also determining if a treatment had any impact on the colony as a whole. Colonies were monitored periodically over 11 months to assess treatment effectiveness by tracking lesion development and overall disease status.

"Success in treating stony coral tissue loss disease with antibiotics may benefit from using approaches typically successful against bacterial infections in humans, for example using a strong initial dose of antibiotics followed by a regimen of smaller supplementary doses over time," said Joshua Voss, Ph.D., senior author, an associate research professor at FAU Harbor Branch and executive director of the NOAA Cooperative Institute for Ocean Exploration, Research, and Technology. "Future research efforts should focus on assessing the potential unintended consequences of antibiotic treatments on corals, their microbial communities, and neighboring organisms. In addition, further efforts are needed to optimize dosing and delivery methods for antibiotic treatments on stony coral tissue loss disease-affected corals and scale up intervention treatments effectively."

Voss notes that many coral diseases are still poorly characterized, which has led to calls for increased research and intervention efforts to support adaptive management strategies particularly given the considerable impacts of diseases on coral reefs over the past five decades.

"Results of our experiment expand management options during coral disease outbreaks and contribute to overall knowledge regarding coral health and disease," said Voss.

This research is part of a highly coordinated collaboration through the Disease Advisory Committee (DAC) organized by the Florida Department of Environmental Protection (floridadep.gov/rcp/coral/content/stony-coral-tissue-loss-disease-response) and NOAA. Voss and Shilling are members of the DAC and part of the reconnaissance and intervention team that has collaboratively developed treatment methods, research objectives, and responses to this disease outbreak. Researchers from Nova Southeastern University, Smithsonian Marine Station and the Florida Fish and Wildlife Conservation Commission also are major partners on this team.

Ian Combs, M.S., another recent FAU graduate from Voss's lab and a co-author, helped to develop some of the coral fate-tracking techniques used in the study.

"We recommend that coral reef managers and intervention specialists, particularly those focusing on stony coral tissue loss disease, adopt 3D photogrammetric methods to ensure that data are more accurate than 2D and in-water estimates," said Combs.

Stimulus-responsive supramolecular structures have emerged as an alternative to conventional ones, owing to their applications in sensing, drug delivery, and switchable memory systems. Now, scientists at Tokyo Institute of Technology explore the hydrostatic-pressure response of "foldamers"--artificial molecules that mimic protein folding--and report a shift in their preferred conformation with changing pressure, demonstrating hydrostatic pressure-enabled dynamic control. The finding opens doors to future development of pressure-sensitive foldamers and artificial materials.

Most, if not all, biological systems are extremely complex and often rely on interactions traditional chemistry does not focus on. An entire field of research called "supramolecular chemistry" has been inspired to study exactly those interactions that govern biological processes, based on an approach relying on artificial "molecular machines" to mimic biological functions. These molecular machines are responsive to a wide range of external stimuli, such as temperature, surrounding media, excitation with light, and consequently find applications in sensing, drug delivery, molecular imaging, and switchable memory technology.

However, a particular stimulus--namely, hydrostatic pressure--has long been in fashion due to the remarkable fact that it allows a supramolecular material to be studied both in its unperturbed and pressurized state. In fact, a research group based in Japan, consisting of scientists from Tokyo Institute of Technology (Tokyo Tech), have recently shown that the optical properties and chemical processes in solutions of supramolecular materials can be precisely regulated by hydrostatic pressure.

Inspired by their findings, the group, led by Prof. Gaku Fukuhara from Tokyo Tech and Prof. Hiromitsu Maeda from Ritsumeikan University, moved on to study the effects of pressure on "foldamers"--artificial molecules that mimic proteins. Their findings were published in the journal Chemical Science (doi : 10.1039/D1SC00664A). The name "foldamer" derives from the fact that these systems can replicate proteins folding into well-defined patterns. Prof. Gaku Fukuhara explains the motivation for their study: "The solution-state behavior of foldamers under hydrostatic pressure has not been examined in detail, which poses a challenge to further advancements in supramolecular chemistry."

For a foldamer to fold into a specific conformation, it first needs to bind to a "guest" negatively charged ion that forms the racemic state (equal amount) of helical structures. The chirality (or the property of being distinct from its mirror image) of the resulting structure can then be induced by introducing an asymmetric counter positive ion, a process known as "ion pairing". The ion pairing, however, depends on the solvation conditions for the foldamer, which, in turn, can be influenced by hydrostatic pressure. Accordingly, scientists chose a fluorescent foldamer as a negative ion receptor, called a "host", and chiral ion pairs (such as chloride and bromide) as "guests" (Fig. 1) to explore the optical properties of the "host" solution under hydrostatic pressure.

The scientists began by examining the changes in fluorescence and absorption (in UV and visible) spectra for the host in various organic solvents under pressure and observed a gradual shift in the spectral band to longer wavelengths as well as an increased absorbance with rising pressure. They attributed this to the fact that the host initially adopts two conformers, one extended and one folded, and gradually shifts to an "extended-rich state" upon pressurization (Fig. 2, left). Then, after electronic excitation (hυ), two different fluorescence states were observed from these conformers (Fig. 2, right).

"Our study clearly shows that conformations in the flexible foldamer host can be dynamically controlled, in both ground and excited states, simply by changing hydrostatic pressure," comments an excited Prof. Fukuhara. "In fact, this strategy can even be extended to other foldamer and guest combinations that have difficulty sensing each other or do not show a host-guest chemistry," he adds.

The team's efforts at deciphering foldamers better certainly brings us one step closer to comprehending the complexity of proteins!

Animals use their sense of smell to navigate the world--to find food, sniff out mates and smell danger. But when a hungry animal smells food and a member of the opposite sex at the same time, what makes dinner the more attractive option? Exactly what is it about the odor of food that says, "Choose me?"

Research by investigators at Harvard Medical School illuminates the neurobiology that underlies food attraction and how hungry mice choose to pay attention to one object in their environment over another.

In their study, published March 3 in Nature, Stephen Liberles and co-author Nao Horio, identified the pathway that promotes attraction to food odors over other olfactory cues.

In a series of experiments, the investigators homed in on a signaling molecule called neuropeptide-Y (NPY), secreted by hunger-regulating neurons into a region of the brain known as the thalamus, which regulates a range of physiologic functions, including relaying sensory information to the cortex.

"It turns out that specific neurons 'listen' to hunger state through the release of a neurotransmitter called NPY in the thalamus," said Liberles, professor of cell biology in the Blavatnik Institute at HMS and an investigator at the Howard Hughes Medical Institute.

Deciding between food and romance

"In mice, both food odors and sex pheromones are attractive, but are relevant for different physiological drives," said Horio, a postdoctoral researcher in the Liberles lab. "This suggests that odors activate parallel neural circuits that are shaped by physiological need."

To pinpoint the pathway that enables a mouse to make need-based decisions, Horio constructed an experiment. To start, she placed mice in an enclosure with two odor ports: one that emitted the smell of mouse chow and the other exuding pheromones from a mouse of the opposite sex. Horio noted the length of time a mouse spent lingering over each port, with longer time indicating the animal's preference.

Fed mice with full tummies found food odors and pheromones similarly attractive, but hungry mice displayed a strong preference for food odors, the scientists observed. Fed mice that had been previously exposed to a potential mate showed a distinct preference for the sex pheromones, whereas hungry mice did not. Why did hunger change the choice?

Illuminating the chemistry of food attraction

Neurons in the hypothalamus, a tiny almond-shaped gland buried deep in the brain, emit a molecule known as agouti-related peptide (AGRP). These neurons are known to trigger the drive for food. To study the effect of AGRP-secreting neurons, the researchers used a technique known as optogenetics, which allows scientists to switch neurons on and off by using light. The experiments showed that even in fed animals, AGRP neuronal activation propelled mice to investigate food odors as though they were famished.

AGRP neurons have branches that spread far and wide, so the researchers wondered which areas of the brain were being stimulated. Further experiments demonstrated that multiple AGRP neuron terminals throughout the brain were activated, but only terminals located in a region known as the paraventricular thalamus changed food odor preference. When they did, mice that were not hungry became attracted to food. Conversely, silencing AGRP projections in this area of the thalamus decreased food-odor attraction in hungry mice.

"This observation led us to believe that the persistent stimulation of AGRP neurons that occurs during fasting enhances food-odor attraction by continually signaling downstream neurons," Liberles said.

The final obstacle was to identify whether any of the three principal neurotransmitters released by AGRP neurons--AGRP, NPY, and GABA--were required for hunger-dependent odor attraction, and if so, which one.

To find out, Liberles and Horio repeated the experiments with three groups of mice--each one genetically modified to lack one of these neurotransmitters.

Hungry mice lacking AGRP and GABA remained attracted to food odor. However, hungry animals that lacked NPY were no longer more attracted to food odors than they were to pheromones. NPY knockout mice, whether their bellies were full or not, retained a lower level of attraction to food odors comparable to their attraction to pheromones. Furthermore, mice lacking a specific NPY receptor, NPY5R, also lost hunger-dependent attraction to food odor.

Moreover, after being exposed to a mate, mice lacking NPY were more attracted to pheromones than food, a finding suggesting that mechanisms other than NPY are involved in tickling the olfactory response to pheromones, Liberles said.

The state of hunger, the study suggests, initiates a complex signaling cascade that, by rendering food aromas appetizing, drives animals to seek nourishment and make food a more attractive option than other alternatives. The experiments demonstrate that the unifying signals in this cascade are NPY and its receptor NPY5R. Moving forward, future research will investigate how NPY acts on some olfactory circuits but not others and how animals learn to associate foods with certain odors.

"It seems likely that different neurotransmitters function as spotlights for other behavioral drives, with the thalamus serving as a switchboard that gives preferential attention to sensory inputs on the basis of physiological need," Liberles said.

STUDY SHOWS VACCINES MAY PROTECT AGAINST NEW COVID-19 STRAINS ... AND MAYBE THE COMMON COLD

A new study by Johns Hopkins Medicine researchers provides evidence that CD4+ T lymphocytes -- immune system cells also known as helper T cells -- produced by people who have received either of the two messenger RNA (mRNA) vaccines for COVID-19 caused by the original SARS-CoV-2 strain also will recognize the mutant variants of the coronavirus that are rapidly becoming the dominant types worldwide.

The researchers say this suggests that T cell responses elicited or enhanced by the vaccines should be able to control the current SARS-CoV-2 variants without needing to be updated or modified. They also found that the same T cells may provide some protection from another member of the coronavirus family that is responsible for one type of the common cold.

The findings were reported April 6, 2021, in the Journal of Clinical Investigation.

CD4+ T cells get their "helper" nickname because they assist another type of immune cell, the B lymphocyte (B cell), in responding to surface proteins -- antigens -- on cells infected by invaders that include viruses such as SARS-CoV-2. Activated by the CD4+ T cells, immature B cells become either plasma cells that produce antibodies to mark infected cells for disposal from the body or memory cells that "remember" the antigen's biochemistry for a faster response to future infections.

In the case of SARS-CoV-2, the antigen is the protein making up the spikes that protrude from the surface of the virus. The mRNA vaccines -- known by their manufacturer's names, Pfizer-BioNTech and Moderna -- provide genetic instructions to a vaccinated person's immune system to recognize the spike protein and start production of antibodies against SARS-CoV-2.

CD4+ T cells also send out chemical messengers that attract another type of T cell -- known as the CD8+ T cell (or "killer T cell") -- so that the virus-infected cells can be removed.

To conduct their helper T cell study, the researchers evaluated blood samples from 30 healthy health care workers and laboratory donors who had not previously tested positive for SARS-CoV-2 -- both before and after two doses of a COVID-19 mRNA vaccine. The participants, 12 women and 18 men, ranged in age from 20 to 59.

CD4+ T cells extracted from the blood samples were analyzed for their responses to various components (protein fragments known as peptides) from the original strain SARS-CoV-2 spike protein and three common cold coronaviruses.

The researchers discovered that vaccine recipients -- as expected -- had broad T cell responses to the original strain SARS-CoV-2 spike peptides.

"We identified 23 distinct T cell-targeted peptides, of which only four appear affected by the mutations that created the variant coronaviruses first seen in the United Kingdom and South Africa," says study senior author Joel Blankson, M.D., Ph.D., professor of medicine at the Johns Hopkins University School of Medicine. "That means the other 19 peptides are the same in the original SARS-CoV-2 and the newer strains, so the mRNA vaccines should induce T cells that respond well to the variants."

Blankson says this is important because previous studies showed that antibodies don't recognize the SARS-CoV-2 variants as well as the CD4+ T cells.

"So the T cells may help prevent the variant viruses from causing severe COVID-19 disease even if antibodies don't stop them from infecting a person," he explains.

When the researchers looked at the vaccine-induced T cell response to the spike proteins of three common cold coronaviruses, they saw a three-fold increase for one, HCoV-NL63, but not the other two.

"Further studies are needed to determine why this occurred," says Blankson. "We suspect that HCoV-NL63 may have more epitopes [peptides that elicit an immune response] in common with SARS-CoV-2 than the other common cold coronaviruses."

In a recent and related study, Blankson and Johns Hopkins Medicine colleagues looked at blood from convalescent patients who had recovered from a SARS-CoV-2 infection and identified the unique receptors on memory CD4+ T cell that recognize the spike proteins of both the original strain of SARS-CoV-2 and four common cold coronaviruses.

Blankson says that characterizing these T cell receptors may be helpful in guiding development of future vaccines for a variety of coronaviruses.

Blankson is available for interviews.

Surrey, B.C. Canada and Rochester, Minn., U.S. (April 22, 2021) - Neuroscience researchers at Mayo Clinic Orthopedics and Sports Medicine in Rochester, Minnesota, U.S., the Health and Technology District and Simon Fraser University (SFU) in Surrey, British Columbia, Canada have published the latest results of their ongoing multi-year hockey concussion study examining changes in subconcussive cognitive brain function in male youth ice hockey players.

The research team monitored brain vital signs during pre- and post-season play in 23 Bantam (age 14 or under) and Junior A (age 16 to 20) male ice-hockey players in Rochester, Minnesota.

"Brain vital signs" translates complex brain waves measured using portable electroencephalography (EEG) at the rink-side, into simple, fast, user-friendly and intuitive results that provide an objective evaluation of cognitive brain function. Called the ABCs of brain function, brain vital signs track three well-established neural responses for Auditory sensation (using a response called the N100), Basic attention (using a response called the P300), and Cognitive processing (using a response called the N400).

The study builds on 2019 results published in Brain: A Journal of Neurology that confirmed significant brain vitals sign changes shortly after concussions were diagnosed in Junior A players. Key results of this study showed undetected impairments remained when players were cleared to return to play using current clinical concussion protocols. Notably, the initial study also reported sensitivity to subconcussive impairments in those players who did not sustain a concussion diagnosis over the course of the season.

The current second phase of the study replicated these results and added the Bantam age group. The latest findings were recently published in the peer-reviewed journal Brain Communications in the advanced articles section.

The results of this new Brain Communications study showed:

Significant brain vital sign changes in N100 Auditory sensation and N400 Cognitive processing responses for the pre-to-post season comparison across both groups.

Differences between the Bantam and Junior A ice hockey players showed more changes in the Junior A group.

Importantly, the subconcussive changes were significantly correlated with the number of head impacts over the season across both age groups and consequently showed more subconcussive changes in brain vital signs.

A subconcussive impact is a mechanical force transmitted to the brain below the threshold for a diagnosis of an acute concussive injury. The effects of these low-magnitude impacts may not even be noticeable to the player or to observers on the sideline. Head impacts in the sport of ice hockey typically result from player-to-player or player-to-boards contact due to body checking, collisions and fighting . Some of these impacts are the consequence of foul play, but many of these events also result from routine, legal on-ice behavior.

"Concussion in sports is a major concern for many and our research has shown that having an objective physiological measure of brain function at rink-side is key to detection and managing concussive impacts," says Dr. Aynsley Smith, principal investigator of the study and Associate Professor of Orthopedics at Mayo Clinic in Rochester, Minnesota.

The study, funded in part by USA Hockey, was co-led by Dr. Michael Stuart, Professor of Orthopedics at Mayo Clinic in Rochester, Minnesota. It is also part of a larger concussion research team within Mayo Clinic that includes neurology research leadership from Dr. David Dodick, Professor of Neurology at Mayo Clinic in Phoenix, Arizona, U.S.

Canadian collaborators include neuroscientist Dr. Ryan D'Arcy, an SFU professor and co-founder of the Health and Technology District in Surrey B.C. and Dr. Shaun Fickling, a biomedical engineer, a recent SFU PhD graduate and lead author of the study.

"Our research has shown that repetitive subconcussive impacts triggered compounding effects in brain function changes, which underscores the importance of shifting our thinking and understanding of concussions as a singular acute-injury model to a spectrum of head-impact exposure and effects over time," says Dr. Fickling.

The US-Canadian concussion research team is continuing to advance their collaborative effort.

Says Dr. D'Arcy, "In medicine: you can't treat what you can't measure. With breakthroughs on measurement challenges, we hope to now accelerate treatment innovations for prevention, acute care and extended care concussion management - for all people across a range of different applications. Our partnership is moving into incredibly exciting future steps - stay tuned."

Living away from community and country, Aboriginal families of children with severe burns also face critical financial stress to cover the associated costs of health care and treatment, a new study shows.

An Australian study, led by Flinders researchers Dr Courtney Ryder and Associate Professor Tamara Mackean, found feelings of crisis were common in Aboriginal families with children suffering severe burns, with one family reporting skipping meals and others selling assets to reduce costs while in hospital.

The economic hardship was found to be worse in families who live in rural areas - some households travelling more than five hours for treatment, creating undue financial strain.

Participants included families from SA, NSW and Queensland who are already part of the larger-Australia-wide Coolamon study on burns injuries in Aboriginal and Torres Strait Islander children.

Their children had sustained severe burns that required at least one night in hospital and follow up care.

So far, the Coolamon study has explored the health inequity of burns incidents and severity in Aboriginal children, with hospitalisation rates found to be 2-3 times greater than other Australian children.

This research conducted by Flinders University in conjunction with The George Institute for Global Health and UNSW School of Population Health also found Aboriginal and Torres Strait Islander children spent five times longer in hospital.

Dr Courtney Ryder, from Flinders University's College of Medicine and Public Health, says out-of-pocket health expenditure are costs not covered by Medicare or health insurance, and could include gap payments, pharmaceutical costs, and travel costs such as transport, car parking, food, and accommodation.

She says results were "astounding" with some families reaching credit card limits, not paying other bills or even selling assets to get by.

"Even though we have Medicare, there are always additional out-of-pocket expenses for health care, and I don't think it's understood the depth or breadth of cost for those Aboriginal families who have a child with an acute burns injury," Dr Ryder says.

"Burns injuries are quite intensive, very invasive and require a lot of follow up. While the expenses might be as simple as sterilised water and bandages, quite often there are additional expenses such as costs associated with travelling away from home.

"One family spoke about having to spend $700 each time they went to town, and they were even staying with family close to the tertiary setting."

Participants also reported not being made aware of government initiatives, such as the Patient Assisted Travel Scheme (PATS), aimed at South Australians who need to travel more than 100km to access medical services.

Dr Ryder says a review of PATS is needed, as Aboriginal and Torres Strait Islanders often face barriers in accessing the scheme, including families who still live in regional areas but within the 100km range.

"There was one family who, because of where they were located, couldn't get assistance through PATS," she says.

"They were having to travel for an hour or more every day to the hospital, then there were parking costs and time spent away from work, so it was still significant."

Despite the stress and financial burden reported by participants, they often commented on the significant role their family networks played in helping and keeping them away from significant financial burden.

The human immune defense is based on the ability of white blood cells to accurately identify disease-causing pathogens and to initiate a defense reaction against them. The immune defense is able to recall the pathogens it has encountered previously, on which, for example, the effectiveness of vaccines is based. Thus, the immune defense the most accurate patient record system that carries a history of all pathogens an individual has faced. This information however has previously been difficult to obtain from patient samples.

The learning immune system can be roughly divided into two parts, of which B cells are responsible for producing antibodies against pathogens, while T cells are responsible for destroying their targets. The measurement of antibodies by traditional laboratory methods is relatively simple, which is why antibodies already have several uses in healthcare.

"Although it is known that the role of T cells in the defense response against for example viruses and cancer is essential, identifying the targets of T cells has been difficult despite extensive research," says Satu Mustjoki, Professor of Translational Hematology.

AI helps to identify new key-lock pairs

T cells identify their targets in a key and a lock principle, where the key is the T cell receptor on the surface of the T cell and the key is the protein presented on the surface of an infected cell. An individual is estimated to carry more different T cell keys than there are stars in the Milky Way, making the mapping of T cell targets with laboratory techniques cumbersome.

Researchers at Aalto University and the University of Helsinki have therefore studied previously profiled key-lock pairs and were able to create an AI model that can predict targets for previously unmapped T cells.

"The AI model we created is flexible and is applicable to every possible pathogen - as long as we have enough experimentally produced key-lock pairs. For example, we were quickly able to apply our model to coronavirus SARS-CoV-2 when a sufficient number of such pairs were available," explains Emmi Jokinen, M.Sc. and a Ph.D. student at Aalto University.

The results of the study help us to understand how a T cell applies different parts of its key to identify its locks. The researchers studied which T cells recognize common viruses such as influenza-, HI-, and hepatitis B -virus. The researchers also used their tool to analyze the role of T-cells recognizing hepatitis B, which had lost their killing ability after the progression of hepatitis to hepatic cell cancer.

The study has been published in the scientific journal PLOS Computational Biology.

A new life for published data with novel AI models

Tools generated by AI are cost-effective research topics.

"With the help of these tools, we are able to make better use of the already published vast patient cohorts and gain additional understanding of them," points out Harri Lähdesmäki, Professor of Computational Biology and Machine Learning at Aalto University.

Using the artificial intelligence tool, the researchers have figured out, among other things, how the intensity of the defense reaction relates to its target in different disease states, which would not have been possible without this study.

"For example, in addition to COVID19 infection, we have investigated the role of the defense system in the development of various autoimmune disorders and explained why some cancer patients benefit from new drugs and some do not", reveals M.D. Jani Huuhtanen, a Ph.D. student at the University of Helsinki, about the upcoming work with the new model.

New research by the University of New England's Palaeoscience Research Centre suggests juvenile tyrannosaurs were slenderer and relatively faster for their body size compared to their multi-tonne parents.

The research, published in the Journal of Vertebrate Paleontology, analysed a collection of fossilised tyrannosaur footprints to learn more about the way these animals aged and how they moved.

UNE PhD student and study leader, Nathan Enriquez -- in international collaboration with the Philip J. Currie Dinosaur Museum, University of Alberta, Royal Ontario Museum, University of Bologna and the Grande Prairie Regional College -- believes the findings contribute a new line of evidence to previous findings based on bone anatomy and computer models of muscle masses.

"The results suggest that as some tyrannosaurs grew older and heavier, their feet also became comparably more bulky," Mr Enriquez said.

"Fully grown tyrannosaurs were believed to be more robust than younger individuals based on their relatively shorter hind limbs and more massive skulls, but nobody had explored this growth pattern using fossil footprints, which are unique in that they can provide a snapshot of the feet as they appeared in life, with outlines of the soft, fleshy parts of the foot that are rarely preserved as fossils.

Footprints can be ambiguous and hard to interpret correctly -- the shape of a footprint may be influenced by the type of ground surface that is stepped on and the motions of the animal making the footprints. In addition, the exact identity of the animal may not always be clear. These challenges have previously limited the use of fossil footprints in understanding dinosaur growth.

The answer lay in the Grande Prairie region of Northern Alberta, Canada, where the research team worked with well-preserved samples of footprints of different sizes that are suggested to belong to the same type of animal.

"We explored a remote dinosaur footprint site where we discovered a new set of large carnivorous dinosaur footprints within very similar rocks to those which have produced tyrannosaur tracks in the past," Mr Enriquez said.

"Based on the relatively close proximity between these discoveries and their nearly equivalent ages -- about 72.5 million years old -- we suggest they may indeed belong to the same species.

"We were also careful to assess the quality of preservation in each footprint, and only considered specimens which were likely to reflect the shape of the actual feet that produced them."

Once the team had a suitable sample, they analysed the outlines of each specimen using a method called geometric morphometrics. This process removes the effect of overall size differences between each footprint and shows what the most important differences in track shape are.

"The greatest difference in shape was found to be the relative width and surface area of the heel impression, which significantly increased in size between smaller and larger footprints," Mr Enriquez said.

"The smaller tracks are comparably slender, while the biggest tyrannosaur tracks are relatively broader and had much larger heel areas. This makes sense for an animal that is becoming larger and needs to support its rapidly increasing body weight. It also suggests the relative speed of these animals decreased with age.

"Increasingly bulky feet in the adults aligns with previous suggestions that juvenile tyrannosaurs would have been faster and more agile for their body size in comparison to their parents, and means that we can add footprints as another line of evidence in the debate over tyrannosaur growth.

"Lastly, it demonstrates the usefulness of footprints for investigating a potentially wider range of ideas about the lives of extinct species than has been considered previously."

Over the last 60 years, scientists have been able to observe how and when genetic information was replicated, determining the existence a "replication timing program", a process that controls when and in what order segments of DNA replicate. However, scientists still cannot explain why such a specific timing sequence exists. In a study published today in Science, Dr. David Gilbert and his team have answered this 60-year-old question.

"Why would cells care about the order in which they replicate DNA?" asked lead scientist Dr. Gilbert. "After all - all cells need to replicate all their DNA. Our hypothesis has been that it's not just DNA that replicates, but all of the regulatory molecules that read the DNA replicate as well." Dr. Gilbert further hypothesized that there might be a purpose behind the replication timing program and process because "mother nature would not squander this opportunity to control how the DNA is read."

"The time at which you replicate provides an ideal time at which to choose whether to maintain all the regulatory factors and continue with the same functional interpretation of the information in DNA or change it to elicit new functions," explains Dr. Gilbert.

Over the last 13 years, Dr. Gilbert and his team showed that each type of cell had a unique replication timing program and that diseased cells had distinct alterations in the program. In this study, Dr. Gilbert and his team looked at how changes in the replication timing program impact the packing of DNA with its regulatory factors, collectively known as the epigenome. The epigenome are regulatory factors that are believed to control the "identity" of the cell, and the functions that the cell will perform.

By eliminating a protein called RIF1, that helps to regulate DNA replication, they found that the replication program was severely and sometimes, almost completely gone so that all segments of chromosomes were replicating at different times in different cells. Without RIF1, if cells were prevented from replicating DNA, their epigenomes were fine. However, as soon as the DNA started to replicate, the regulatory molecules that associate with the DNA became incorporated incorrectly and worsened with each round of DNA replication. Eventually, the 3-dimensional folding of the chromosomes was also altered.

Dr. Gilbert suggests that when the epigenome is disrupted by altering the replication timing program, the cells might no longer perform their normal functions, or they may perform inappropriate functions. These inappropriate functions may have a large and negative impact on a person's health.

"We and others have shown previously that the program is altered in many diseases," says Dr. Gilbert. "Our lab recently showed specific patterns of altered timing that were linked statistically to poor outcomes in pediatric leukemia, and in another study to diseases of premature aging."

Thus, the replication timing program provides a whole new genre of molecular pathways and biomarkers that lead to and identify disease states. This could lead to earlier diagnoses and more accurate prognoses for patients.

While Dr. Gilbert's work has answered one important question, he does not plan to stop here. "We think that the epigenome... is not [only] essential for a cell to just maintain its identity, but we hypothesize that it is critical for cells to turn into other cell types."

Testing this hypothesis is crucial for the fields of stem cell research and the therapeutic application of stem cells. Dr. Gilbert is currently using human stem cells to test how a disrupted replication timing affects development of these cells into liver cells, heart cells, and neurons. The results from this study will provide valuable information for human health and disease studies in the future.

NEW YORK, NY--A new imaging technique developed by scientists at Columbia University Vagelos College of Physicians and Surgeons and St. Jude Children's Research Hospital captures movies of receptors on the surface of living cells in unprecedented detail and could pave the way to a trove of new drugs. 

The researchers used the technique to zoom in on individual receptor proteins on the surface of living cells to determine if the receptors work solo or come together to work as pairs. This work appeared in the April issue of Nature Methods.

"If two different receptors come together to form a dimer with distinctive function and pharmacology, this might allow for a new generation of drugs with greater specificity and reduced side effects," says Jonathan Javitch, MD, PhD, the Lieber Professor of Experimental Therapeutics in Psychiatry at VP&S.  

G-protein coupled receptors (GPCRs) are some of medicine's most important molecules: About one-third of today's drugs work by targeting a GPCR. The possibility that GPCRs form heterodimers--consisting of two different flavors of GPCR--is an especially exciting prospect for the development of better drugs.

"The potential of GPCR heterodimers for improved pharmacotherapies, including for disorders such as schizophrenia and depression, is exciting and has drawn us to the field," Javitch says.

But for decades, scientists have hotly debated whether most GPCRs form dimers or work alone. Much of this impasse stemmed from the relatively poor spatial resolution of current techniques. Different GPCRs in a cell have been captured near each other, but it was unclear if the receptors were working together.

"The controversy over receptor dimerization has only grown fiercer with conflicting data from different labs using different methods," Javitch says.

Using a new, more powerful technique based on single-molecule fluorescence resonance energy transfer (smFRET), Javitch and Scott C. Blanchard from St. Jude Children's and Weill Cornell show that dimers can be tracked as they move on the cell surface and how long they last. This method takes advantage of a change in fluorescence that occurs when proteins, labeled with different fluorescent markers, are extremely close to each other. The resolution in this approach is more than 10 times greater than previous techniques. 

This new and exciting technique entails multiple innovations in dyes, labeling technology, protein engineering, imaging, and software that enabled tracking of individual and coupled receptors. 

Not only does this method detect GPCR dimers, it also allows, for the first time, a clear view of how receptors in a living cell change shape when activated. This will provide researchers a better understanding of how drugs can differentially impact the same receptors. 

"With this method, we can now explore receptor interactions and activation mechanisms with unprecedented resolution, giving us an opportunity to investigate new therapeutic approaches," Javitch says.

PHILADELPHIA, PA - The first National Institutes of Health (NIH) National Cancer Institute (NCI)-funded clinical study examining stereotactic body radiotherapy (SBRT) in the treatment of oligometastatic breast, prostate, and non-small cell lung (NSCLC) cancers displayed evidence that SBRT can be safely used to treat patients who have multiple metastases. These results were recently published in JAMA Oncology.

The results of the Phase I NRG-BR001 trial, conducted by the NCI National Clinical Trials Network group NRG Oncology, indicate that SBRT treatment in standard doses was safe for 35 evaluable patients with a median of 3 metastases. There were no dose-limiting toxicities and over 50% of trial participants were alive at 2 years following treatment.

"Prior to this trial, little to no evidence was available to support that SBRT is a safe and tolerable treatment option for patients who have multiple metastases. Researchers have hypothesized that SBRT could improve survival outcomes for this patient population; however, it was imperative we determine the safety of this procedure, appropriate dose and scheduling, and how to coordinate across multiple centers the quality assurance of the procedures prior to testing its efficacy," stated Steven J. Chmura, MD, PhD, of the Department of Radiation and Cellular Oncology at the University of Chicago Comprehensive Cancer Center and the lead author of the NRG-BR001 manuscript. "To ensure safety, this trial used an extensive radiation QA process to test the accuracy of treating moving tumors and was the first NRG trial to require the use of 3D image guidance during treatment for soft tissue tumors."

NRG-BR001 enrolled up to 6 evaluable patients for each of the following 7 selected anatomic locations: bone/osseous (BO), spinal/paraspinal (SP), peripheral lung (PL), central lung (CL), abdominal/pelvic (AP), mediastinal/cervical lymph node (MC), and liver (L). As a single patient could contribute to more than one location, the safety question was able to be answered with 35 evaluable patients from the 42 enrolled trial participants. Patients were required to have 3-4 metastases or 2 metastases in close proximity to each other. SBRT starting dose was 50 GY over 5 fractions for the CL and MC groups, 45 GY over 3 fractions for the PL, AP, and L groups and 30 Gy over 3 fractions for the BO and SP group. Additional patients would be accrued as needed at defined de-escalated doses if any of the starting doses were not deemed to be safe.

The 35 evaluable patients had breast (n=12), NSCLC (n=10), and prostate (n=13) cancers. No dose de-escalations were needed. There were 8 instances of grade 3 adverse events. There were no treatment-related deaths.

SBRT for multiple metastases is now utilized in multiple ongoing Phase II and III NCI-sponsored trials. Follow-up research should be done in long surviving oligometastatic patients.

"These are important data from the multicenter study, confirming that complicated stereotactic body radiotherapy to multiple sites is safe and feasible. We eagerly await the results of ongoing, larger randomized trials to demonstrate how effective this is when compared to drug therapy alone for metastatic cancer," stated Mitchell Machtay, MD, the Associate Dean for Clinical Cancer Research at the Penn State College of Medicine and the interim Group Chair for NRG Oncology.