New technique shows in detail where drug molecules hit their targets in the body

A team at Scripps Research invented a new method, called CATCH, that shows how drugs hit their targets in the body. Cells targeted by a drug (pargyline shown in cyan) can be identified by multiple rounds of immunolabeling (red showing neurons; yellow showing dopaminergic/noradrenergic neurons; blue showing cell nuclei). Credit: Scripps Research

Scientists at Scripps Research have invented a way to image, across different tissues and with higher precision than ever before, where drugs bind to their targets in the body. The new method could become a routine tool in drug development.

Described in a paper in Cell on April 27, 2022, the new method, called CATCH, attaches fluorescent tags to molecules and uses chemical techniques to improve the fluorescent signal. The researchers demonstrated the method with several different experimental drugs, revealing where—even within —the drug molecules hit their targets.

“This method ultimately should allow us, for the first time, to see relatively easily why one drug is more potent than another, or why one has a particular side effect while another one doesn’t,” says study senior author Li Ye, Ph.D., assistant professor of neuroscience at Scripps Research and The Abide-Vividion Chair in Chemistry and Chemical Biology.

The study’s first author, Zhengyuan Pang, is a graduate student in the Ye lab. The study also was a close collaboration with the laboratory of Ben Cravatt, Ph.D., Gilula Chair of Chemical Biology at Scripps Research.

“The unique environment at Scripps Research, where biologists routinely work together with chemists, is what made the development of this technique possible,” Ye says.

Understanding where drug molecules bind their targets to exert their —and side effects—is a basic part of . However, drug-target interaction studies traditionally have involved relatively imprecise methods, such as bulk analyses of drug-molecule concentration in entire organs.

The CATCH method involves the insertion of tiny chemical handles into drug molecules. These distinct chemical handles don’t react with anything else in the body, but do allow the addition of fluorescent tags after the have bound to their targets. In part because human or animal tissue tends to diffuse and block the light from these fluorescent tags, Ye and his team combined the tagging process with a technique that makes tissue relatively transparent.

In this initial study, the researchers optimized and evaluated their method for “covalent drugs,” which bind irreversibly to their targets with stable chemical bonds known as covalent bonds. This irreversibility of binding makes it particularly important to verify that such drugs are hitting their intended targets.

The scientists first evaluated several covalent inhibitors of an enzyme in the brain called fatty acid amide hydrolase (FAAH). FAAH inhibitors have the effect of boosting levels of cannabinoid molecules, including the “bliss molecule” anandamide, and are being investigated as treatments for pain and mood disorders. The scientists were able to image, at the single-cell level, where these inhibitors hit their targets within large volumes of mouse brain tissue, and could easily distinguish their different patterns of target engagement.

In one experiment, they showed that an experimental FAAH inhibitor called BIA-10-2474, which caused one death and several injuries in a clinical trial in France in 2016, engages unknown targets in the midbrain of mice even when the mice lack the FAAH enzyme—offering a clue to the source of the inhibitor’s toxicity.

In other tests demonstrating the unprecedented precision and versatility of the new method, the scientists showed that they could combine drug-target imaging with separate fluorescent-tagging methods to reveal the cell types to which a drug binds. They also could distinguish drug-target engagement sites in different parts of neurons. Finally, they could see how modestly different doses of a drug often strikingly affect the degree of target engagement in different brain areas.

The proof-of-principle study is just the beginning, Ye emphasizes. He and his team plan to develop CATCH further for use on thicker tissue samples, ultimately perhaps whole mice. Additionally, they plan to extend the basic approach to more common, non-covalently-binding drugs and chemical probes. On the whole, Ye says, he envisions the new method as a basic tool not only for drug discovery but even for basic biology.

“In situ Identification of Cellular Drug Targets in Mammalian Tissue” was co-authored by Zhengyuan Pang, Michael Schafroth, Daisuke Ogasawara, Yu Wang, Victoria Nudell, Neeraj Lal, Dong Yang, Kristina Wang, Dylan Herbst, Jacquelyn Ha, Carlos Guijas, Jacqueline Blankman, Benjamin Cravatt and Li Ye—all of Scripps Research during the study.



More information:
Zhengyuan Pang et al, In situ identification of cellular drug targets in mammalian tissue, Cell (2022). DOI: 10.1016/j.cell.2022.03.040

Journal information:
Cell



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New technique shows in detail where drug molecules hit their targets in the body (2022, April 29)
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Study shows advances in street lighting are reducing the efficacy of coastal species’ camouflage

An illustration of how a Littornid snail loses the benefit of camouflage making it more visible under broad spectrum lighting (right). Credit: University of Plymouth

Species that rely on darkness to forage and feed are losing the gift of camouflage thanks to advances in the lighting used to illuminate the world’s cities and coastlines, a study has shown.

The worldwide proliferation of energy efficient broad lighting has the potential to disrupt an array of visually guided .

New research has demonstrated that these new lighting technologies can significantly improve a predator’s ability to discriminate prey species against a natural background.

The magnitude of this effect varies depending on an organism’s color, meaning certain color variations may be at greater risk.

The study, published in the Journal of Applied Ecology, was conducted by researchers at the University of Plymouth and Plymouth Marine Laboratory (PML).

It is one of the first to examine the potential for artificial light at night (ALAN) to affect the camouflage mechanisms of coastal species.

Oak McMahon, who led the research while studying for an MSc in Applied Marine Science and is now a Ph.D. candidate at the University of Plymouth, said: “This study clearly indicates that new lighting technologies will increase the conspicuousness of by reducing the efficacy of their camouflage. Our findings revealed that species of Littorinid snails found commonly on our coastlines will remain camouflaged when illuminated by older style lighting. However, when illuminated by modern broad spectrum lighting, they are clearly visible to predators and at far greater long-term risk as a result.”

Funded by the Natural Environment Research Council, this is the latest research by the University and PML to highlight the growing levels of ALAN and its impacts on coastal environments.

For this study, scientists used a well-established model to determine the conspicuousness of three distinct color morphs of Littorinid snail found commonly along the world’s coastlines.

Street lighting creates an artificial glow in the night sky above Plymouth and the surrounding areas. Credit: Thomas Davies, University of Plymouth

They compared how the species appeared to three common coastal predators when illuminated by different forms of lighting. This included 20th century narrow spectrum Low Pressure Sodium (LPS) lighting, three types of modern broad spectrum lighting—High Pressure Sodium (HPS); Light Emitting Diodes (LEDs); and Metal Halide (MH) – and the provided by the sun and moon.

Under LPS lighting, all snails were effectively camouflaged. However, when illuminated by LEDs, MH, the sun or the moon, yellow snails were significantly more visible compared to brown and olive ones in the majority of cases.

Dr. Thomas Davies, Lecturer in Marine Conservation at the University of Plymouth and the study’s senior author, said: “As technologies develop, there has been a shift from narrow spectrum to lighting that enables us to live and travel in a safe, secure manner. However, estimates suggest that a quarter of the planet between the Arctic Circle and Antarctica is now being affected by night-time light pollution. Some predictions say that LED bulbs will account for 85% of the global street lighting market in around five years, and our study highlights that such advances will have repercussions for humans and animals alike now and in the future.”

Dr. Tim Smyth, PML Head of Science for Marine Biogeochemistry and Observations and co-author on the research, added: “The ability to light our environment around the clock has transformed the urban landscapes over the past century and has ushered in what some call the Urbanocene. The shift from the orange glow over cities, typical of my youth in the 1970s and 80s, has now shifted much more towards energy efficient wide spectrum LEDs which even enables us humans to correctly perceive color. This work shows that this advancement has additional ramifications for the , which is having to adapt at an increasing rate to the artificial changes we are making to the environment. We need to learn to adapt our technologies to avoid the worst consequences of their adoption.”

What can be done to reduce the impact of artificial lighting on our coastlines

With estimates indicating that 23% of the world’s surface, between the planet’s , are affected by ALAN—and a rate of increase of 2.2% between 2012 and 2016—the need to address the situation is pressing to say the least.

In the study, the researchers highlight a variety of mitigation methods available to planners and environmental managers when considering its ecological impacts.

These include reducing the amount of light used, shielding lights to reduce their effects on the surrounding environment, employing part-night lighting during times of peak demand, and manipulating the spectra of lighting to minimize ecological impacts.

The researchers highlight that while it may seem intuitive to suggest using narrow spectrum lighting to avoid these impacts, the effects of ALAN extend beyond those seen on camouflage and that all parts of the visual spectrum will likely have some ecological impact.



More information:
Oak McMahon et al, Broad spectrum artificial light at night increases the conspicuousness of camouflaged prey, Journal of Applied Ecology (2022). DOI: 10.1111/1365-2664.14146

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Study shows advances in street lighting are reducing the efficacy of coastal species’ camouflage (2022, March 26)
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Model shows how antibodies navigate pathogen surfaces like a child at play

Antibodies aim to establish a foothold on two separate antigens, in much the same way a child might try navigating stepping stones in a stream. Credit: Ian Hoffecker

A new study shows how antibodies select the antigens that they bind to, as they navigate the surface of pathogens like coronaviruses. Researchers from KTH Royal Institute of Technology and Karolinska Institutet have created a model that suggests the migration of these pathogen hunters may be akin to the random movements of a child playing on a stream laden with stepping stones.

Ian Hoffecker, a researcher at KTH Royal Institute of Technology in Stockholm, says the model raises new ways to consider the evolution of viruses and immune systems, and that the new study yields insights that may be useful in vaccine engineering.

Antibodies are often thought of as Y-shaped proteins. But recent studies have shown that perhaps a more accurate way to envision them is to flip the picture upside down and regard as walking stick figures, stepping on antigens. Those two characteristic “Y” branches function as legs of sorts, Hoffecker says.

Paraphrasing Nancy Sinatra’s 1966 hit recording, he says: “These antibodies are made for walking.”

These stalking pathogen hunters mark their prey by planting their “feet” on antigens— scattered like stepping stones in various patterns on the surfaces of viruses. They rely on what’s called multivalence—or establishing a foothold with both “Y” branches, typically on two separate antigens—which allows them to bind as strongly as possible to their targets. Once in place, antibodies participate in a series of interactions with other signaling proteins to neutralize or kill the pathogen.

Using a nano-fabricated model of a pathogen’s antigen pattern, the researchers set out to determine how this behavior is influenced by pathogen surfaces, Hoffecker says. “What if antigens are really close together or what if they’re kind of far apart? Do the antibodies’ molecules stretch out, do they compress?”

To find out, Björn Högberg from Karolinska Institutet’s Division of Biomaterials Research says the team simulated a pathogen and antigen scenario using a method called DNA origami, in which DNA self-assembles into nanostructures with a programmable geometry that allowed them to control the distance between antigens.

“This tool has enabled us to investigate how this distance between two antigens impacts binding strength,” Högberg says. “In our new work we took this data and plugged it into a model that lets us ask interesting questions about how antibodies behave in more complex environments—without straying too far from reality.”

Hoffecker says the model reveals that antibodies behave not much differently from another well-known bipedal organism—namely, human beings.

“The process could be likened to a child playing on a river laden with stepping stones just large enough to accommodate a single foot,” Hoffecker says. “So to stand in place, the child would have to straddle two rocks or else balance on one foot.”

The antibodies in the seemed to favor antigens that are closer together and easier to stand on. And if are too far apart, they have a statistical tendency to migrate to an area where they stand closer together, he says.

Such observations raise the question of whether the flexibility and structure of antibodies is influenced by their antagonists, the pathogens. “We are asking the question, is this relevant to evolution, or co-evolution, where you have this constant arms race between the and pathogens, and this control system that basically says how antibodies move and where they go?” he says.

Hoffecker says the next steps are to observe how this property of antibodies manifests itself in , and to incorporate these findings into rationally-designed vaccines that account for the antigen spatial organization factor.

The research was published in Nature Computational Science.



More information:
Ian Hoffecker et al, Stochastic modeling of antibody binding predicts programmable migration on antigen patterns, Nature Computational Science (2022). DOI: 10.1038/s43588-022-00218-z. www.nature.com/articles/s43588-022-00218-z

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Model shows how antibodies navigate pathogen surfaces like a child at play (2022, March 24)
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Hexbyte Glen Cove Research shows climate cooling affects how human societies thrive or decline

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Ruins of Palenque. Image: Jan Harenburg/Wikipedia.

Human civilizations depend on the climate. Changes in climate affect the production of food and other resources that support our populations and economies. Paul Hooper, alumnus and adjunct associate professor of anthropology at The University of New Mexico, recently published Human Social Complexity Was Significantly Lower during Climate Cooling Events of the Past 10 Millennia in Cliodynamics: The Journal of Quantitative History and Cultural Evolution. The research confirms that human civilizations thrive or decline depending on the climate around them.

In the 1990s, American geologist Gerard Bond uncovered the signal of climate cooling events based on the expansion of ice sheets in the North Atlantic. The Seshat dataset is a cross-cultural database published by a team from Oxford and the University of Connecticut that contains historical information about societies all over the world, including a measure of social complexity. Hooper reanalyzed this dataset to examine how complexity during cooling periods compared to other periods.

Social complexity is a set of characteristics that typically come together in large-scale societies, including population size, government, writing, and urbanization. Social complexity has tended to increase over the last 10,000 years, particularly after the transition to agriculture, he noted.

“I looked at how much human civilizations were affected by climate cooling events that occurred repeatedly over the past 10,000 years. I found that societies were substantially less complex during the coldest centuries of these climate events. For societies in northern regions, cooling was associated with a loss of about 300 years of accumulated ,” Hooper explained.

“The research shows that the success of civilizations depends on favorable climatic conditions. Departures from these conditions are associated with stagnation and collapse. The historical record makes it clear,” Hooper said. Average temperatures were roughly 2 degrees Celsius (4 degrees Fahrenheit) colder during cooling events.

“Societies based on agriculture, like our own, are productive within a surprisingly narrow range of ,” Hooper said. “Too cold, too hot, or too little water, and productivity suffers. Complex societies have never faced the climate conditions that are now on the horizon, and they’re going to be a shock to our social and economic systems. In addition to higher , precipitation will also be key. While some areas will dry up, others will receive more water due to higher rates of evaporation from the oceans.”



More information:
The paper is available for download here.

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Research shows climate cooling affects how human societies thrive or decline (2022, March 14)
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Hexbyte Glen Cove New study shows the largest comet ever observed was active at near-record distance

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The comet Bernardinelli-Bernstein (BB), represented in this artist rendition as it might look in the outer Solar System, is estimated to be about 1000 times more massive than a typical comet. The largest comet discovered in modern times, it is among the most distant comets to be discovered with a coma, which means ice within the comet is vaporizing and forming an envelope of dust and vapor around the comet’s core. Credit: NOIRLab / NSF / AURA / J. da Silva / Spaceengine

A new study by University of Maryland astronomers shows that comet Bernardinelli-Bernstein (BB), the largest comet ever discovered, was active long before previously thought, meaning the ice within it is vaporizing and forming an envelope of dust and vapor known as a coma. Only one active comet has been observed farther from the sun, and it was much smaller than comet BB.

The finding will help astronomers determine what BB is made of and provide insight into conditions during the formation of our solar system. The finding was published in The Planetary Science Journal on November 29, 2021.

“These observations are pushing the distances for active comets dramatically farther than we have previously known,” said Tony Farnham, a research scientist in the UMD Department of Astronomy and the lead author of the study.

Knowing when a becomes active is key to understanding what it’s made of. Often called “dirty snowballs” or “icy dirtballs,” comets are conglomerations of dust and ice left over from the formation of the solar system. As an orbiting comet approaches its closest point to the sun, it warms, and the ices begin to vaporize. How warm it must be to start vaporizing depends on what kind of ice it contains (e.g., water, carbon dioxide, carbon monoxide or some other frozen compound).

Scientists first discovered comet BB in June 2021 using data from the Dark Energy Survey, a collaborative, international effort to survey the sky over the Southern hemisphere. The survey captured the bright nucleus of the comet but did not have high-enough resolution to reveal the envelope of dust and vapor that forms when the comet becomes active.

At 100 km across, comet BB is the largest comet ever discovered by far, and it is farther from the sun than the planet Uranus. Most comets are around 1 km or so and much closer to the sun when they are discovered. When Farnham heard about the discovery, he immediately wondered if images of comet BB had been captured by the Transient Exoplanet Survey Satellite (TESS), which observes one area of the sky for 28 days at a time. He thought TESS’s longer exposure times could provide more detail.

Farnham and his colleagues combined thousands of images of comet BB collected by TESS from 2018 through 2020. By stacking the images, Farnham was able to increase the contrast and get a clearer view of the comet. But because comets move, he had to layer the images so that comet BB was precisely aligned in each frame. That technique removed the errant specks from individual shots while amplifying the image of the comet, which allowed researchers to see the hazy glow of surrounding BB, proof that BB had a and was active.

To ensure the coma wasn’t just a blur caused by the stacking of images, the team repeated this technique with images of inactive objects from the Kuiper belt, which is a region much farther from the sun than comet BB where icy debris from the early solar system is plentiful. When those objects appeared crisp, with no blur, researchers were confident that the faint glow around comet BB was in fact an active coma.

The size of comet BB and its distance from the sun suggests that the vaporizing ice forming the coma is dominated by carbon monoxide. Since carbon monoxide may begin to vaporize when it is up to five times farther away from the sun than comet BB was when it was discovered, it is likely that BB was active well before it was observed.

“We make the assumption that comet BB was probably active even further out, but we just didn’t see it before this,” Farnham said. “What we don’t know yet is if there’s some cutoff point where we can start to see these things in cold storage before they become active.”

According to Farnham, the ability to observe processes like the formation of a cometary coma farther than ever before opens an exciting new door for astronomers.

“This is just the beginning,” Farnham said. “TESS is observing things that haven’t been discovered yet, and this is kind of a test case of what we will be able to find. We have the potential of doing this a lot, once a comet is seen, going back through time in the images and finding them while they are at farther distances from the sun.”



More information:
Tony L. Farnham et al, Early Activity in Comet C/2014 UN271 Bernardinelli–Bernstein as Observed by TESS, The Planetary Science Journal (2021). DOI: 10.3847/PSJ/ac323d

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New study shows the largest comet ever observed was active at near-record distance (2021, November 29)
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Hexbyte Glen Cove Study shows political ideology determines health behavior, especially during pandemic

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Credit: Unsplash/CC0 Public Domain

When considering determinants of an individual’s health outcomes, doctors and researchers consider personal factors like age, race, gender or socioeconomic factors such as education quality, economic stability or health care access. A new study from the University of Kansas adds to the evidence that political ideology can be a social determinant of health, especially during public health crises.

Researchers have long considered that a person’s association with an ideological view may have bearing on on a long-term basis, such as embracing bans on public smoking to prevent lung cancer, or opposing vaccines due to concerns about secondary effects, but the COVID-19 pandemic provided a unique opportunity to study how it plays into during a public emergency. For the study, the authors conducted two surveys and a on ideology and health, finding that did influence attitudes and health behavior during the pandemic.

“What this study shows is political partisanship and ideology seem to be one of the most significant drivers of health behavior when it comes to COVID-19,” said lead author Mugur Geana, associate professor of journalism and director of KU’s Center for Excellence in Health Communications to Underserved Populations. “The U.S. Department of Health and Human Services defines social determinants of health as the conditions in the environments where people are born, live, learn, play, worship and age that affect a wide range of . Because ideology depends on group affiliation and influences interpersonal relationships, we think it should also be considered a social determinant of health.”

That finding is especially important to remember in a time of significant political polarization in the United States, wrote Geana and co-authors Nathaniel Rabb and Steven Sloman of The Policy Lab at Brown University. The study was published in the journal SSM-Population Health.

For the study, researchers first conducted a convenience sample survey on social media through the Center for Excellence and Health Communications to Underserved Populations, followed by a survey with a nationally representative sample through Brown’s Policy Lab. Respondents were asked about their political ideological beliefs as well as their knowledge of COVID-19, attitudes and beliefs related to COVID-19 risk factors, and demographic information. The surveys, conducted in late 2020, also asked where people received information on the pandemic, if they intended to get vaccinated, if they had COVID-19 themselves or knew anyone who did, if they wore masks and practiced social distancing, and other related questions. Data analysis from both surveys suggested that ideology was a significant predictor for all dependent behavioral variables, and in most cases, the strongest one.

For the third part of the study, authors conducted a review of 181 papers on the emerging COVID-19 behavioral literature and analyzed the results from 44 selected studies that examined ideology’s influence on health behaviors. It was shown to be a significant predictor of responses in 79% of the studies’ estimates, and it had the largest effect on COVID-19 related behaviors in 39% of these. No other variable, such as age, gender, education or race/ethnicity, was the best predictor in nearly as many studies.

The three sources of data, taken together, contribute to the growing body of knowledge that individuals’ will influence how they behave in relation to their own health and that of the public. That has significant potential ramifications on public health as well as for health policy and strategic communications.

“It was obvious we expected to see differences in attitudes and behaviors based on political partisanship, but we wanted to know how much of an impact it has, and if our findings reflect those from other studies,” Geana said. “Much to our surprise, we found that ideology was the best predictor of COVID-19 related behavior. When we take that all in, it suggests that in times of crisis, which the pandemic was, and in a polarized society, ideology is a significant driver of how people behave when it comes to their health.”

Geana said the study was not intended and should not be used to advocate for any ideology or argue that any ideology is right or wrong. The purposed was to contribute to the body of knowledge of how ideology influences health behavior in times of crises and to create awareness about this phenomenon for policymakers, health officials and health communicators, especially in the hyperpolarized climate of the United States.

Geana has conducted similar studies into how Kansas residents received information on the pandemic and assessed risk, as well as comparing how the United States and Chile, two seemingly different nations, approached the crisis. Together, these studies show the importance of considering multiple variables, including ideology or political partisanship, when assessing health behavior, and promotes understanding that one message will not resonate equally with all in terms of health interventions and when addressing the valid concerns people may have in regard to their health.

“This shows we need to keep an open mind and be sure the messages for the health interventions we are designing are appropriate for the audience we are trying to reach at that moment in time,” Geana said.



More information:
Mugur V. Geana et al, Walking the party line: The growing role of political ideology in shaping health behavior in the United States, SSM – Population Health (2021). DOI: 10.1016/j.ssmph.2021.100950

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Hexbyte Glen Cove Study shows a whale of a difference between songs of birds and humpbacks thumbnail

Hexbyte Glen Cove Study shows a whale of a difference between songs of birds and humpbacks

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Credit: CC0 Public Domain

Decades of research have been dedicated to understanding humpback whale songs. Why do they sing? What and where is the intended audience of these songs? To help uncover the answers, many scientists have framed whale songs as something similar to bird songs: vocalizations designed for attracting potential mates, or warnings to competitors.

But for the past several years, a University at Buffalo researcher has been proposing a radically different story about whale songs. His latest study, published in the journal Animal Cognition, presents additional evidence to strengthen his argument for a departure from treating whale songs as the underwater analog to bird songs.

The findings reveal the changing nature of the units within whale songs, and the way those units further morph through the years. These changes present a vocal flexibility that demonstrates the inadequacy of using human labels, likes cries, chirps and moans, for a species with the capacity for much more sophisticated sound production.

“The analyses in this paper suggest that we shouldn’t be thinking about whale songs as language or musical notes,” says Eduardo Mercado, Ph.D., a professor of psychology in UB’s College of Arts and Sciences. “What the singers are doing seems to be much more dynamic, both within songs and across years.

“Maybe it’s a matter of switching from thinking about whale songs as to something more freeform, like dancing.”

Current hypotheses assume whales combine sounds (units) into patterns (phrases) to construct the displays (songs) that reveal their fitness to possible mates. From this perspective, Mercado says, single units are like individual quills in a peacock’s tail, each functionally equal, and useful only as a collective.

But the units are not functionally equal, according to Mercado’s paper, co-written with Christina E. Perazio, an assistant professor at the University of New England. The unit morphing produces some units that are much less detectable than others, a finding that challenges previous conclusions regarding fitness in favor of the songs instead revealing locations and movements, with each change making relevant units easier to hear across long distances.

To help make his point, Mercado alludes to the revision made to the barnyard moral code in George Orwell’s “Animal Farm” in the title of his paper, suggesting that some humpback units “are more equal than others.”

“There are clear differences in the units when listening to whale songs from different years,” says Mercado. “They’re so different that it’s like switching from one musical genre to another. In any given year, the whales are using an altogether different set of sounds.”

So, what’s going on? Is it all random?

Not likely, according to Mercado.

Mercado relied on a method that collected detailed measures of variations in units produced by singers and then compared those measures to characteristics produced in different years. This approach emphasized variability in vocal behavior rather than summaries of “unit types.”

“These changes are what got me interested in ,” says Mercado. “I was trying to understand how they get away with this. If they’re changing sounds, how are other whales making sense of those changes? Imagine people with no preparation just shifting languages several times over a 10-year span and everyone continuing to understand everyone else despite that variation.”

The changes appear evolutionary in nature, not random. The modifications adhere to a clear set of rules, like maintaining pitch ranges even when the sounds appear subjectively to be varying quite a bit. The morphing of these units might contribute to the overall function of the songs, possibly by increasing the number of positions from which listening can reliably detect, localize and track them.

That flexibility further reveals the shortcomings inherent in subjective or computational methods for sorting units into discrete categories that don’t capture nuances of vocalizations.

“These labels are a bad idea,” says Mercado. “Shifts in pitch and duration might force an incorrect re-categorization of units. We might think we’re hearing something different, but the whale might be saying nothing has changed.”

Mercado adds, “Humans are not the gold standard for distinguishing sounds, and we have to acknowledge and respect that when conducting research.”



More information:
Eduardo Mercado et al, All units are equal in humpback whale songs, but some are more equal than others, Animal Cognition (2021). DOI: 10.1007/s10071-021-01539-8

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Hexbyte Glen Cove New study shows the potential of DNA-based data-structures systems thumbnail

Hexbyte Glen Cove New study shows the potential of DNA-based data-structures systems

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A double stranded DNA fragment. Credit: Vcpmartin/Wikimedia/ CC BY-SA 4.0

Newcastle University research offers important insights into how we could turn DNA into a green-by-design data structure that organises data like conventional computers.

The team, led by researchers from Newcastle University’s School of Computing, created new dynamic DNA data structures able to store and recall information in an ordered way from DNA molecules. They also analysed how these structures are able to be interfaced with external nucleic acid computing circuits.

Publishing their findings in the journal Nature Communications, the scientists present an in vitro implementation of a stack data structure using DNA polymers. Developed as a DNA chemical reaction system, the stack system is able to record combinations of two different DNA signals (0s and 1s), release the signals into solution in reverse order, and then re-record.

The stack, which is a linear data structure which follows a particular order in which the operations are performed, stores and retrieves information (DNA signal strands) in a last-in first-out order by building and truncating DNA “polymers” of single ssDNA strands. Such a stack data structure may eventually be embedded in an in vivo context to store messenger RNAs and reverse the temporal order of a translational response, among other applications.

Professor Natalio Krasnogor, of Newcastle University’s School of Computing, who led the study explains: “Our civilisation is data hungry and all that information processing thirst is having a strong environmental impact. For example, pollute more than the aviation industry, the top 7000 in the world use around 2% of global electricity and we all heard about the environmental footprint of some cryptocurrencies.

“In recent years DNA has been shown to be an excellent substrate to store data and the DNA is a renewable, sustainable resource. At Newcastle we are passionate about sustainability and thus we wanted to start taking baby steps into green-by-design molecular information processing in DNA and go beyond simply storing data. We wanted to be able to organise it. In computer science, data structures are at the core of all the algorithms that run our modern economy; this is so because you need a way to have a unified and standardised way to operate on the data that is stored. This is what data structures enable. We are the first to demonstrate a molecular realisation of this crucial component of the modern information age.”

Information processing at the nanoscale level

Study co-author, Dr. Annunziata Lopiccolo, Research Associate at Newcastle University’s Centre for Synthetic Biology and the Bioeconomy, added: “If we start thinking about data storage, immediately our minds picture electronic microchips, USB drives and many other existing technologies. But over the last few years biologists challenged the data storage media sector demonstrating that the DNA nature, as a highly stable and resilient media, can function as a quaternary data storage, rather than binary. In our work we wanted to demonstrate that it is possible to use the quaternary code to craft readable inputs and outputs under the form of programmable signals, with a linear and organised data structure. Our work expands knowledge in the context of information processing at the nanoscale level.”

Study co-author Dr. Harold Fellermann, Lecturer at Newcastle University School of Computing, added: “Our biomolecular data structure, where both data as well as operations are represented by short pieces of DNA, has been designed with biological implementations in mind. In principle, we can imagine such a device to be used inside a living cell, bacteria for example. This makes it possible to bring to domains that are currently hard to access with traditional silicon-based, electronic computing. In the future, such data structures might be used in environmental monitoring, bioremediation, green production, and even personalised nanomedicine.”

Study co-author, Dr. Benjamin Shirt-Ediss, Research Associate, Newcastle University School of Computing, said: “It was really interesting to develop a computational model of the DNA chemistry and to see good agreement with experimental results coming out of the lab. The computational model allowed us to really get a handle on the performance of the DNA stack data structure—we could systematically explore its absolute limits and suggest future avenues for improvement.”

The experimental DNA stack system constitutes proof-of principle that a polymerising DNA chemistry can be used as a dynamic data to store two types of DNA signal in a last-in first-out order. While more research is needed to determine the best-possible way to archive and access DNA-based data, the study highlights the enormous potential of this technology, and how it could help tackle the rapidly growing data demands.



More information:
Annunziata Lopiccolo et al, A last-in first-out stack data structure implemented in DNA, Nature Communications (2021). DOI: 10.1038/s41467-021-25023-6

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Hexbyte Glen Cove Study shows common insecticide is harmful in any amount thumbnail

Hexbyte Glen Cove Study shows common insecticide is harmful in any amount

Hexbyte Glen Cove

An alfalfa leafcutter bee, the type used by UC Riverside scientists to study the effects of pesticide and water levels. Credit: David Rankin/UCR

A new UC Riverside study shows that a type of insecticide made for commercial plant nurseries is harmful to a typical bee even when applied well below the label rate.

The study was published today in the journal Proceedings of the Royal Society B: Biological Sciences.

Chemically similar to nicotine, neonicotinoids are insecticides that protect against plant-consuming insects like aphids, but seriously harm beneficial insects, like bees. They are widely used by commercial growers.

Much research has focused on their use in like canola, in which they are typically applied at low doses. However, this study is one of the few to examine neonicotinoid application in potted ornamental , which can represent more potent, acute sources of exposure to the toxin for bees.

“Neonicotinoids are often used on food crops as a seed treatment,” explained UCR entomologist and lead study author Jacob Cecala. “But they’re usually applied in higher amounts to ornamental plants for aesthetic reasons. The effects are deadly no matter how much the plants are watered.”

Cecala said he was surprised by this result, given that neonicotinoids are water soluble. Going into the study, he assumed that more water would dilute the amount of harm they caused the bees. The researchers were also curious whether increased watering could benefit bees despite insecticide exposure by increasing the quantity or quality of nectar offered by the plants.

To test these assumptions, the researchers raised bees on flowering in pots that either received a lot of watering, or a little. Plants were selected based on their popularity at nurseries, drought tolerance to ensure blooming even without much water, and their attractiveness to bees. In addition, half the plants were treated with the insecticide.

Though increased water decreased the pesticide’s potency in the nectar of the flowers, the on bees were still observed.

“Unfortunately, we observed a 90% decrease in the bees’ reproduction with both high and low levels of irrigation,” Cecala said.

This study is also one of the few to examine neonicotinoid effects via on solitary bees, which make up more than 90% of native bee species in North America, and an even higher percentage in California.

Female alfalfa leafcutter bees construct nests composed of individual cells, like these. Credit: Jacob Cecala/UCR

Solitary bees are not bees who have left the hive and are now alone. This is a type of bee that lives alone, does not produce honey, and does not have a queen or live in a hive. Because they do not have a store of honey to protect, they are also not aggressive.

“Solitary bees are more representative of the ecosystem here, and they are potentially more vulnerable to pesticides,” said UCR entomologist and study co-author Erin Rankin.

If a worker bee that is social—like the honeybee—gets exposed to insecticide and dies, it won’t necessarily affect the longevity of the hive. However, if a solitary bee dies, its lineage is cut short.

In this study, the researchers used alfalfa leafcutter bees, which make their nests in tunnels and lay eggs one at a time. They are very similar to California’s solitary native bees and are part of a genus that can be found worldwide.

The first time Cecala and Rankin tried this experiment, they used the concentration of insecticide recommended on the product label. All the bees died in a matter of days.

The next time they ran the experiment, they used a third of the recommended dose and still found negative effects on reproduction, the ability of the bees to feed themselves, and overall fitness. “It almost completely wiped them out,” Cecala said.

Though this study used a neonicotinoid product formulated for nurseries, formulations of similar products for home gardeners also tend to be highly concentrated.

Plants in nurseries or residential backyards represent a smaller total area than food plant fields like corn or soy. However, high-potency products can have a big effect even in small areas. In 2013, neonicotinoids applied to flowering trees in a retail parking lot in Oregon caused a massive bumblebee die off, with more than 25,000 found dead.

The researchers recommend that nurseries quantify the amount of pesticides that are making their way into flowers given their watering and pesticide regimes, and consider alternative management practices that reduce harm to bees and the ecosystems dependent on them.

“It’s not as simple as ‘don’t use pesticides’—sometimes they’re necessary,” Cecala said. “However, people can look for a different class of insecticide, try to apply them on plants that aren’t attractive to bees, or find biological methods of pest control.”



More information:
Jacob M. Cecala et al, Pollinators and plant nurseries: how irrigation and pesticide treatment of native ornamental plants impact solitary bees, Proceedings of the Royal Society B: Biological Sciences (2021). DOI: 10.1098/rspb.2021.1287

Citation:
Study shows common insecticide is harmful in any amount (2021, August 2)
retrieved 2 August 2021
from https://phys.org/news/2021-08-common-insecticide-amount.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.

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Hexbyte Glen Cove 'Designer' pore shows selective traffic to and from the cell nucleus thumbnail

Hexbyte Glen Cove ‘Designer’ pore shows selective traffic to and from the cell nucleus

Hexbyte Glen Cove

The team reduced the complexity of nuclear pores down to a single, artificial Nucleoporin that they call ‘NupX’. This protein is based on the average properties of a class of Nucleoporins rich in the amino acid motif Glycine-Leucine-Phenylalanine-Glycine. In these simulation snapshots, each particle represents a whole amino acid. Credit: University of Groningen

The nucleus is the headquarters of a cell and molecules constantly move across the nuclear membrane through pores. The transport of these molecules is both selective and fast; some 1,000 molecules per second can move in or out. Scientists from the University of Groningen and Delft University of Technology, both in the Netherlands, and a colleague from the Swedish Chalmers University of Technology, have developed an artificial model of these pores using simple design rules, which enabled them to study how this feat is accomplished. Their results were published on 31 March in Nature Communications.

Nuclear pores are extremely complicated structures. The pore itself is a big protein complex and the opening of the pore is filled with a dense network of disordered proteins called nucleoporins. These proteins regulate selective transport, but exactly how they do this is still unclear. “The nuclear pore complex is one of the biggest structures in the cell,” explains Patrick Onck, professor of Micromechanics at the University of Groningen. “We previously studied the pores in all their complexity, but for this study, we created a drastically simplified ‘designer’ pore to investigate the essential physical mechanisms of transport.”

Nanopore

First, the team analyzed the composition of the nucleoporins to design a simplified, ‘average’ version, which they termed nucleoporin X, or NupX for short. These proteins are made up of domains comprising phenylalanine (F) and glycine (G) amino acids in tandem, and these play an essential role in transport. These FG repeats are separated by ‘spacers’ of other amino acids. In addition to the FG repeats, some nucleoporins also contain domains of glycine, leucine, phenylalanine and glycine, or GLFG repeats. The team designed proteins that contain both domains, separated by spacers of ten amino acids.

NupX was tested in two different systems: it was studied experimentally, attached to a surface and added to artificial nanopores that were ‘drilled’ in a ‘membrane’ of silicon nitride, and through . The experiments were performed at Delft University of Technology, while the simulations were prepared and executed in Groningen, mostly by Henry de Vries, a Ph.D. student in Onck’s laboratory.

Snapshot of the computer simulations, showing that nanopores filled with NupX-proteins allow specific transport proteins (chaperones) to pass. At the same time, the pores efficiently block any non-specific molecules. Credit: University of Groningen

Transport ticket

The nucleoporins were tested for interactions with non-specific proteins and with chaperones, which are proteins that act as transport tickets through the pore. In the cell, large molecules that must be transported into or out of the nucleus can only do so when they are attached to such a chaperone. The artificial nucleoporins selectively interacted with the chaperones but not with the non-specific proteins. This demonstrated that the NupX pores are fully functional: they are able to facilitate selective transport. De Vries: “However, the experiments showed that transport through the artificial pores occurs but not what happens inside the pore. With our simulations, we showed what exactly happens inside the pore as the chaperones translocate, while the non-specific proteins do not interact with the pore at all.”

The simulations also revealed how the FG and the GLFG nucleoporins were distributed inside the pore. “Recent studies suggested that they would be in different places in and that this might help to create selectivity,” says De Vries. “However, we found that they were homogenously distributed and yet we still saw selectivity.” Another suggestion was that the amino acids that make up the spacers are important for the selectivity. “Our results showed that the specific sequence of amino acids in the spacer doesn’t matter since we used random sequences. The only important part is the ratio of charged amino acids to hydrophobic within the spacers, which determines the stickiness of the proteins.”

Redundancy

The final conclusion of the study is that a very simple system in nucleoporins that has limited variation still produces a selective pore. “What is needed is a certain density of these FG nucleoporins,” says Onck. “These form a barrier, which can only be breached by the chaperones.” This begs the question of why the pores contain a very large number of different nucleoporins in nature. Onck: “We know that nature doesn’t always come up with optimized solutions. However, their redundancy could very well have a function in natural pores.”

The fact that the very simple artificial system already reproduces selective transport mechanisms means that the scientists now have an excellent tool to study the physical principles that regulate nuclear function. Onck: “This could lead to new fundamental insights but also to new applications, for example in creating filtration systems, or in the design of artificial cells.”



More information:
Alessio Fragasso et al, A designer FG-Nup that reconstitutes the selective transport barrier of the nuclear pore complex, Nature Communications (2021). DOI: 10.1038/s41467-021-22293-y

Citation:
‘Designer’ pore shows selective traffic to and from the cell nucleus (2021, March 31)
retrieved 31 March 2021
from https://phys.org/news/2021-03-pore-traffic-cell-nucleus.html

This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no
part may be reproduced without the written permission. The content is provided for information purposes only.

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