The World Health Organization describes antibiotic-resistant bacteria as one of the greatest threats to global health. To deal with the problem, there needs to be a shift in the way we use antibiotics, and new, sustainable medical technologies must be developed.

“After testing our new hydrogel on different types of bacteria, we observed a high level of effectiveness, including against those which have become resistant to antibiotics,” says Martin Andersson, research leader for the study and Professor at the Department of Chemistry and Chemical Engineering at Chalmers University of Technology.

Research and development of the material has been ongoing for many years at Martin Andersson’s group at Chalmers, growing in scope along the way, with a particular focus on the possibilities for wound care. Now, the important results are published as a scientific article in the journal ACS Biomaterials Science & Engineering.

The main purpose of the studies so far has been to explore new medical technology solutions to help reduce the use of systemic antibiotics. Resistant bacteria cause what is referred to as hospital-acquired infection — a life-threatening condition and is increasing in incidence worldwide.

Mimicking the natural immune system

The active substance in the new bactericidal material consists of antimicrobial peptides, small proteins which are found naturally in our immune system.

“With these types of peptides, there is a very low risk for bacteria to develop resistance against them, since they only affect the outermost membrane of the bacteria. That is perhaps the foremost reason why they are so interesting to work with,” says Martin Andersson.

Researchers have long tried to find ways to use these peptides in medical devices, but so far without much success. The problem is that they break down quickly when they come into contact with bodily fluids such as blood. The current study describes how the researchers managed to overcome the problem through the development of a nanostructured hydrogel, into which the peptides are permanently bound, creating a protective environment.

“The material is very promising. It is harmless to the body’s own cells and gentle on the skin. In our measurements, the protective effect of the hydrogel on the antimicrobial peptides is clear — the peptides degrade much slower when they are bound to it,” says Edvin Blomstrand, doctoral student at the Department of Chemistry and Chemical Engineering at Chalmers, and one of the main authors of the article.

“We expected good results, but we were really positively surprised at quite how effective the material has proven,” adds Martin Andersson.

According to the researchers, this new material is the first medical device to make successful use of antimicrobial peptides in a clinically and commercially viable manner. There are many varied and promising opportunities for clinical application.

Startup company Amferia takes the research from lab to market

In recent years, foundational research into the antimicrobial peptide hydrogel has run in parallel with commercial development of the innovation through the spin-off company Amferia AB.

The company was founded in 2018 by Martin Andersson together with Saba Atefyekta and Anand Kumar Rajasekharan, who both defended their dissertations at Chalmers’ Department of Chemistry and Chemical Engineering.

The material and the idea, which is currently developed as an antibacterial wound patch, has generated interest around the world, attracting significant investment and receiving several awards. The company is working intensively to get the material to market so that it can benefit wider society.

Before the new material can benefit hospitals and patients, clinical studies are needed, which are ongoing. A CE marking of the material is expected to be completed in 2022. Furthermore, the wound patch version of the new material is undergoing trials in veterinary care, for treating pets. The company Amferia AB is already collaborating with a number of veterinary clinics around Europe where the hydrogel is now being tested.

“Amferia has recently entered into a strategic partnership with Sweden’s largest distributor of premium medical & diagnostic devices to jointly launch these wound care products for the Swedish veterinary market during 2021” says Martin Andersson.

More about antimicrobial peptides and the new material

The beneficial properties of antimicrobial peptides have been known for some decades, and thousands of different varieties occurring in the natural immune systems of humans, animals and plants have been discovered. Researchers have long tried to mimic and use their natural function to prevent and treat infections without having to use traditional antibiotics. However, because the peptides are broken down as soon as they come in contact with blood or other body fluids, successful clinical usage has proved elusive. The researchers knew that smart new solutions were needed to protect the peptide from degradation. The new material in the study has been shown to work very well, allowing the peptides to be applied directly to wounds and injuries on the body, with the effect of both preventing and treating infection. The material is also non-toxic, so it can be used directly on the skin. The potential of this new material can also be seen in the flexibility that it offers for different types of products.

“So far, we have mainly envisioned the material as a wound care dressing, but we are working on a new study investigating the potential for a wound care spray,” says Edvin Blomstrand.

Now, after performing an extensive comparative genomics study, MIT researchers have generated what they describe as the most accurate and complete gene annotation of the SARS-CoV-2 genome. In their study, which appears today in Nature Communications, they confirmed several protein-coding genes and found that a few others that had been suggested as genes do not code for any proteins.

“We were able to use this powerful comparative genomics approach for evolutionary signatures to discover the true functional protein-coding content of this enormously important genome,” says Manolis Kellis, who is the senior author of the study and a professor of computer science in MIT’s Computer Science and Artificial Intelligence Laboratory (CSAIL) as well as a member of the Broad Institute of MIT and Harvard.

The research team also analyzed nearly 2,000 mutations that have arisen in different SARS-CoV-2 isolates since it began infecting humans, allowing them to rate how important those mutations may be in changing the virus’ ability to evade the immune system or become more infectious.

Comparative genomics

The SARS-CoV-2 genome consists of nearly 30,000 RNA bases. Scientists have identified several regions known to encode protein-coding genes, based on their similarity to protein-coding genes found in related viruses. A few other regions were suspected to encode proteins, but they had not been definitively classified as protein-coding genes.

To nail down which parts of the SARS-CoV-2 genome actually contain genes, the researchers performed a type of study known as comparative genomics, in which they compare the genomes of similar viruses. The SARS-CoV-2 virus belongs to a subgenus of viruses called Sarbecovirus, most of which infect bats. The researchers performed their analysis on SARS-CoV-2, SARS-CoV (which caused the 2003 SARS outbreak), and 42 strains of bat sarbecoviruses.

Kellis has previously developed computational techniques for doing this type of analysis, which his team has also used to compare the human genome with genomes of other mammals. The techniques are based on analyzing whether certain DNA or RNA bases are conserved between species, and comparing their patterns of evolution over time.

Using these techniques, the researchers confirmed six protein-coding genes in the SARS-CoV-2 genome in addition to the five that are well established in all coronaviruses. They also determined that the region that encodes a gene called ORF3a also encodes an additional gene, which they name ORF3c. The gene has RNA bases that overlap with ORF3a but occur in a different reading frame. This gene-within-a-gene is rare in large genomes, but common in many viruses, whose genomes are under selective pressure to stay compact. The role for this new gene, as well as several other SARS-CoV-2 genes, is not known yet.

The researchers also showed that five other regions that had been proposed as possible genes do not encode functional proteins, and they also ruled out the possibility that there are any more conserved protein-coding genes yet to be discovered.

“We analyzed the entire genome and are very confident that there are no other conserved protein-coding genes,” says Irwin Jungreis, lead author of the study and a CSAIL research scientist. “Experimental studies are needed to figure out the functions of the uncharacterized genes, and by determining which ones are real, we allow other researchers to focus their attention on those genes rather than spend their time on something that doesn’t even get translated into protein.”

The researchers also recognized that many previous papers used not only incorrect gene sets, but sometimes also conflicting gene names. To remedy the situation, they brought together the SARS-CoV-2 community and presented a set of recommendations for naming SARS-CoV-2 genes, in a separate paper published a few weeks ago in Virology.

Fast evolution

In the new study, the researchers also analyzed more than 1,800 mutations that have arisen in SARS-CoV-2 since it was first identified. For each gene, they compared how rapidly that particular gene has evolved in the past with how much it has evolved since the current pandemic began.

They found that in most cases, genes that evolved rapidly for long periods of time before the current pandemic have continued to do so, and those that tended to evolve slowly have maintained that trend. However, the researchers also identified exceptions to these patterns, which may shed light on how the virus has evolved as it has adapted to its new human host, Kellis says.

In one example, the researchers identified a region of the nucleocapsid protein, which surrounds the viral genetic material, that had many more mutations than expected from its historical evolution patterns. This protein region is also classified as a target of human B cells. Therefore, mutations in that region may help the virus evade the human immune system, Kellis says.

“The most accelerated region in the entire genome of SARS-CoV-2 is sitting smack in the middle of this nucleocapsid protein,” he says. “We speculate that those variants that don’t mutate that region get recognized by the human immune system and eliminated, whereas those variants that randomly accumulate mutations in that region are in fact better able to evade the human immune system and remain in circulation.”

The researchers also analyzed mutations that have arisen in variants of concern, such as the B.1.1.7 strain from England, the P.1 strain from Brazil, and the B.1.351 strain from South Africa. Many of the mutations that make those variants more dangerous are found in the spike protein, and help the virus spread faster and avoid the immune system. However, each of those variants carries other mutations as well.

“Each of those variants has more than 20 other mutations, and it’s important to know which of those are likely to be doing something and which aren’t,” Jungreis says. “So, we used our comparative genomics evidence to get a first-pass guess at which of these are likely to be important based on which ones were in conserved positions.”

This data could help other scientists focus their attention on the mutations that appear most likely to have significant effects on the virus’ infectivity, the researchers say. They have made the annotated gene set and their mutation classifications available in the University of California at Santa Cruz Genome Browser for other researchers who wish to use it.

“We can now go and actually study the evolutionary context of these variants and understand how the current pandemic fits in that larger history,” Kellis says. “For strains that have many mutations, we can see which of these mutations are likely to be host-specific adaptations, and which mutations are perhaps nothing to write home about.”

The research was funded by the National Human Genome Research Institute and the National Institutes of Health. Rachel Sealfon, a research scientist at the Flatiron Institute Center for Computational Biology, is also an author of the paper.

Gem-quality diamonds are nearly pure lattices of carbon. This elemental purity gives them them their luster; but it also means they carry very little information about their ages and origins. However, some lower-grade specimens harbor imperfections in the form of tiny pockets of liquid — remnants of the more complex fluids from which the crystals evolved. By analyzing these fluids , the scientists in the new study worked out the times when different diamonds formed, and the shifting chemical conditions around them.

“It opens a window — well, let’s say, even a door — to some of the really big questions” about the evolution of the deep earth and the continents, said lead author Yaakov Weiss, an adjunct scientist at Columbia University’s Lamont-Doherty Earth Observatory, where the analyses were done, and senior lecturer at the Hebrew University of Jerusalem. “This is the first time we can get reliable ages for these fluids.” The study was published this week in the journal Nature Communications.

Most diamonds are thought to form some 150 to 200 kilometers under the surface, in relatively cool masses of rock beneath the continents. The process may go back as far as 3.5 billion years, and probably continues today. Occasionally, they are carried upward by powerful, deep-seated volcanic eruptions called kimberlites. (Don’t expect to see one erupt today; the youngest known kimberlite deposits are tens of millions of years old.)

Much of what we know about diamonds comes from lab experiments, and studies of other minerals and rocks that come up with the diamonds, or are sometimes even encased within them. The 10 diamonds the team studied came from mines founded by the De Beers company in and around Kimberley, South Africa. “We like the ones that no one else really wants,” said Weiss — fibrous, dirty-looking specimens containing solid or liquid impurities that disqualify them as jewelry, but carry potentially valuable chemical information. Up to now, most researchers have concentrated on solid inclusions, such as tiny bits of garnet, to determine the ages of diamonds. But the ages that solid inclusions indicate can be debatable, because the inclusions may or may not have formed at the same time as the diamond itself. Encapsulated fluids, on the other hand, are the real thing, the stuff from which the diamond itself formed.

What Weiss and his colleagues did was find a way to date the fluids. They did this by measuring traces of radioactive thorium and uranium, and their ratios to helium-4, a rare isotope that results from their decay. The scientists also figured out the maximum rate at which the nimble little helium molecules can leak out of the diamond — without which data, conclusions about ages based on the abundance of the isotope could be thrown far off. (As it turns out, diamonds are very good at containing helium.)

The team identified three distinct periods of diamond formation. These all took place within separate rock masses that eventually coalesced into present-day Africa. The oldest took place between 2.6 billion and 700 million years ago. Fluid inclusions from that time show a distinct composition, extremely rich in carbonate minerals. The period also coincided with the buildup of great mountain ranges on the surface, apparently from the collisions and squishing together of the rocks. These collisions may have had something to do with production of the carbonate-rich fluids below, although exactly how is vague, the researchers say.

The next diamond-formation phase spanned a possible time frame of 550 million to 300 million years ago, as the proto-African continent continued to rearrange itself. At this time, the liquid inclusions show, the fluids were high in silica minerals, indicating a shift in subterranean conditions. The period also coincided with another major mountain-building episode.

The most recent known phase took place between 130 million years and 85 million years ago. Again, the fluid composition switched: Now, it was high in saline compounds containing sodium and potassium. This suggests that the carbon from which these diamonds formed did not come directly from the deep earth, but rather from an ocean floor that was dragged under a continental mass by subduction. This idea, that some diamonds’ carbon may be recycled from the surface, was once considered improbable, but recent research by Weiss and others has increased its currency.

One intriguing find: At least one diamond encapsulated fluid from both the oldest and youngest eras. The shows that new layers can be added to old crystals, allowing individual diamonds to evolve over vast periods of time.

It was at the end of this most recent period, when Africa had largely assumed its current shape, that a great bloom of kimberlite eruptions carried all the diamonds the team studied to the surface. The solidified remains of these eruptions were discovered in the 1870s, and became the famous De Beers mines. Exactly what caused them to erupt is still part of the puzzle.

The tiny diamond-encased droplets provide a rare way to link events that took place long ago on the surface with what was going on at the same time far below, say the scientists. “What is fascinating is, you can constrain all these different episodes from the fluids,” said Cornelia Class, a geochemist at Lamont-Doherty and coauthor of the paper. “Southern Africa is one of the best-studied places in the world, but we’ve very rarely been able to see beyond the indirect indications of what happened there in the past.”

When asked whether the findings could help geologists find new diamond deposits, Weiss just laughed. “Probably not,” he said. But, he said, the method could be applied to other diamond-producing areas of the world, including Australia, Brazil, and northern Canada and Russia, to disentangle the deep histories of those regions, and develop new insights into how continents evolve.

“These are really big questions, and it’s going to take people a long time to get at them,” he said. “I will go to pension, and still not have finished that walk. But at least this gives us some new ideas about how to find out how things work.”

The other authors of the study are Yael Kiro of Israel’s Weizmann Institute of Science; Gisela Winckler and Steven Goldstein of Lamont-Doherty; and Jeff Harris of Scotland’s University of Glasgow.

Unlike animals, the trees that make up our planet’s forests can’t uproot and find new terrain if conditions get tough. Instead, many trees produce seeds and pollen that are designed to be carried away by the wind, an adaptation that helps them colonize new territories and maximize how far they can spread their genes.

The new study compared global wind patterns with previously published genetic data of nearly 100 tree and shrub species collected from forests around the world, finding significant correlations between wind speed and direction and genetic diversity throughout our planet’s forests. The findings are the first to show that wind may not only influence the spread of an individual tree or species’ genes, but it can also help shape genetic diversity and direct the flow of gene variants across entire forests and landscapes.

Understanding how genetic variants move throughout a species range will become increasingly important as climate change alters the conditions of local habitats, the researchers say.

“How trees move and how plants move, in general, is a big area of uncertainty in plant ecology because it’s hard to study plant movements directly — they happen as a result small, rare movements of seeds and pollen,” said study lead author Matthew Kling, a postdoctoral researcher in integrative biology at UC Berkeley. “However, to predict how species distributions, and plant ecology, in general, will respond to climate change, we need to understand how these species are going to be able to move long distances to track the movement of natural resources and climate conditions over time.”

While animals, birds and insects can also disperse pollen and seeds, wind’s strong directionality makes it particularly important for understanding how different tree species will respond to climate change, said study senior author David Ackerly, a professor and dean of UC Berkeley’s Rausser College of Natural Resources.

“As the world warms, many plants and animals will need to move to places with suitable habitat in the future to survive,” Ackerly said. “Wind dispersal has a particularly interesting connection to climate change because wind can either push the genes or organisms in the right direction, toward more suitable habitat, or in the opposite direction. It may be the only terrestrial dispersal vector that can be aligned with or against the direction of climate change.”

Any way the wind blows

Despite the fickle nature of daily weather conditions, large-scale global wind patterns are largely determined by Earth’s shape, rotation and the locations of the continents, and are believed to be relatively stable over millennial time-scales. These wind patterns are also unlikely to be dramatically altered by climate change, Kling said.

To examine whether these global prevailing winds have shaped the genetic diversity of modern-day forests, Kling compared current planetary wind models — compiled from 30 years of global wind data — with genetic data from 72 publications covering 97 tree and shrub species and 1,940 plant populations worldwide.

Kling’s analysis revealed three key ways that global wind patterns are shaping forests’ genetic diversity. First, tree populations that are connected by stronger wind currents tend to be more genetically similar than tree populations that are not as connected. Second, tree populations that are more downwind, or farther in the direction that the wind blows, tend to have more genetic diversity in general. Finally, genetic variants are more likely to disperse in the direction of the wind.

Though these patterns can only be statistically validated by looking at many populations of trees throughout the world, they can sometimes be evident when examining the genetic diversity of a single tree species across its habitat range, Kling said.

For example, the island scrub oak, or Quercus pacifica, is native to the Channel Islands in Southern California, where prevailing winds tend to blow to the southeast. Kling’s analysis showed that scrub oak populations on islands that are connected by higher wind speeds are more genetically similar to each other. Genetic variants also appear to have dispersed more frequently to the islands in the southward and eastward directions than the reverse, leading to greater genetic diversity to the south and east.

Kling hopes that recognizing these patterns will help conservationists and ecologists better understand how well tree and plant species in different regions of the globe will adapt to a warming world.

“Populations in different portions of a species range have evolved over time to be well-adapted to the climate in that specific part of the range, and as climate changes, they can become out of sync with those conditions,” Kling said. “Understanding how quickly genetic variants from elsewhere in the species range can get where they are needed is important for understanding how quickly the species will respond to climate change, and how vulnerable, versus resilient, a given population might be.”

This research was supported by a National Science Foundation Graduate Research Fellowship.

Human parainfluenza viruses, or HPIVs, are the leading cause of childhood respiratory infections, responsible for 30% to 40% of illnesses like croup and pneumonia. The viruses also affect the elderly and people with compromised immune systems.

To sicken people, HPIVs must latch onto cells and inject their genetic material to start making new viruses. HPIV3 is the most prevalent among these viruses. There are currently no approved vaccines or antivirals for HPIV3 infection in people.

In a study led by the Sam Gellman lab in the chemistry department at the University of Wisconsin-Madison, and the lab of Anne Moscona and Matteo Porotto at Columbia University, researchers built upon years of work on peptide treatments to generate one capable of blocking the HPIV3 attachment process.

The researchers published their findings April 7 in the Journal of the American Chemical Society.

To enter host cells, HPIVs use specialized fusion proteins that resemble three corkscrews laid side-by-side. Earlier work by the Moscona-Porotto lab showed that scientists could a partial chunk of this corkscrew protein from HPIV3, introduce this peptide to the virus, and prevent the corkscrew from driving the infection process. The peptide, itself a corkscrew, essentially zippers up with the virus’s corkscrews, creating a tight bundle of six corkscrew shapes.

The new peptide persists longer in the body, making it about three times more effective at blocking infection in rodent models of disease than the original form.

The research team started by trying to engineer the original peptide to be more resistant to protein-digesting enzymes in the body, which can easily shred proteins and make them useless. So, the Gellman lab turned to unusual building blocks to create a hardier peptide.

Cells build proteins out of alpha amino acids. But chemists can create beta amino acids, which are similar but have an extra carbon atom. When peptides use these beta amino acid building blocks, they often take a different shape because of the extra atom. This can help a peptide hide from protein-digesting enzymes and survive longer.

However, the researchers also knew that if the peptide’s shape changed too much as a result of these unusual building blocks, they might not lock together with HPIV’s corkscrew fusion protein.

That’s where the Gellman lab’s decades of experience testing and modifying beta amino acid-containing peptides became critical.

“We know which side of the peptide is binding to its protein target. So, we (knew that we) can modify only residues that are not directly involved in binding the viral protein,” says Victor Outlaw, a postdoctoral researcher in the lab and one of the co-first authors of the report. In lab tests, they saw that the carefully modified peptide still bound strongly to the virus’s protein.

In another improvement pioneered by the Moscona-Porotto lab, the scientists hooked the peptide up to a molecule of cholesterol. This fatty addition helps the peptide slide into the greasy cell membrane, where it can best block the virus.

“Our hypothesis was that the combination of beta amino acids and cholesterol would increase anti-viral efficacy,” says Outlaw, who explained that the cholesterol helped get the peptide to where it needed to go, while the shape change from the beta amino acids allowed the peptide to persist longer in the body.

As the research team hoped, when they gave the new peptide to cotton rats it lasted much longer in the lungs than the previous version did thanks to its resistance to digestion by enzymes. The peptide was delivered into the rats’ noses.

To test how well the peptide worked to prevent infection, cotton rats received the new peptide before they were exposed to HPIV3. Compared to animals given no antiviral peptides, those given the improved peptide had 10 times fewer viruses in their lungs.

And compared to the peptide that was more susceptible to enzymes, the hardier peptide reduced viral load by about three times, suggesting that the new peptide’s ability to avoid digestion in the body helps it better block infection.

While the approach hasn’t yet been tested in humans and researchers must further refine and test the system, it does provide a new strategy for potentially preventing or treating these common infections.

The research collaboration is now looking to make second-generation peptides that last even longer in the body. They also want to test how well the modified peptide might block infection by related viruses. That additional research could move the peptide treatment closer to clinical trials.

“This was a very fortunate coming together of groups that had complementary needs and capabilities,” says Gellman. “It’s really been a great joint effort.”

This work was supported by the National Institutes of Health (grants R01AI114736, R01 GM056414, F32 GM122263 and T32 GM008349.)

When taking a picture with a regular CMOS camera, like the ones on smartphones, the camera sensor is open to a large influx of photons during a predefined exposure time. Each pixel in the sensor grid outputs an analog value that depends on the number of photons that hit that pixel during exposure. However, this type of imaging has few ways to deal with moving objects; the movement of the object has to be much slower than the exposure time to avoid blurring. In contrast, single-photon cameras capture a rapid burst of consecutive frames with very short individual exposure times. These frames are binary — a grid of 1s and 0s that respectively indicate whether one photon arrived at each pixel or not during exposure. To reconstruct an actual picture from these binary frames (or bit planes), many of them have to be processed into a single non-binary image. This can be achieved by assigning different levels of brightness to all the pixels in the grid, depending on how many of the bit planes had a “1” for each pixel.

Besides its higher speed, the completely digital nature of single-photon imaging allows for designing clever image reconstruction algorithms that can make up for technical limitations or difficult scenarios. At Tokyo University of Science, Japan, Professor Takayuki Hamamoto has been leading a research team focused on taking the capabilities of single-photon imaging further. In the latest study by Prof. Hamamoto and his team, which was published in IEEE Access, they developed a highly effective algorithm to fix the blurring caused by motion in the imaged objects, as well as common blurring of the entire image such as that caused by the shaking of the camera.

Their approach addresses many limitations of existing deblurring techniques for single-photon imaging, which produce low-quality pictures when multiple objects in the scene are moving at different speeds and dynamically overlapping each other. Instead of adjusting the entire image according to the estimated motion of a single object or on the basis of spatial regions where the object is considered to be moving, the proposed method employs a more versatile strategy.

First, a motion estimation algorithm tracks the movement of individual pixels through statistical evaluations on how bit values change over time (over different bit planes). In this way, as demonstrated experimentally by the researchers, the motion of individual objects can be accurately estimated. “Our tests show that the proposed motion estimation technique produced results with errors of less than one pixel, even in dark conditions with few incident photons,” remarks Prof. Hamamoto.

The team then developed a deblurring algorithm that uses the results of the motion estimation step. This second algorithm groups pixels with a similar motion together, thereby identifying in each bit plane separate objects moving at different speeds. This allows for deblurring each region of the image independently according to the motions of objects that pass through it. Using simulations, the researchers showed that their strategy produced very crisp and high-quality images, even in low-light dynamic scenes crowded with objects coursing at disparate velocities.

Overall, the results of this study aptly showcase how greatly single-photon imaging can be improved if one gets down to developing effective image processing techniques. “Methods for obtaining crisp images in photon-limited situations would be useful in several fields, including medicine, security, and science. Our approach will hopefully lead to new technology for high-quality imaging in dark environments, like outer space, and super-slow recording that will far exceed the capabilities of today’s fastest cameras,” says Prof. Hamamoto. He also states that even consumer-level cameras might timely benefit from progress in single-photon imaging.

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