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A year ago scientists everywhere were scrambling to get their minds around the SARS-CoV-2, a novel coronavirus that caused the pandemic from which we are only now beginning to emerge. The world clung to every new development, every bit of science that could provide clues to managing life in the presence of this mysterious killer.

Many science-backed COVID-19 management concepts remain unchanged to this day: handwashing with soap and warm water disrupts the virus' lipid membrane. Social distancing can attenuate the virus's spread, ideally keeping it out of a host until it degrades. Other notions, such as droplet contact being the primary mode of transmission, were modified when emerging evidence showed that under certain conditions, the virus could remain suspended in air for extended periods of time.

In a letter(link is external) in the Journal of Infectious Diseases, a team of researchers from UC Santa Barbara, Oregon State University, University of Manchester and ETH Zurich examines another of SARS-CoV-2's well known characteristics -- its vulnerability to sunlight. Their conclusion? It might take more than UV-B rays to explain sunlight inactivation of SARS-CoV-2.

The idea that an additional mechanism might be in play came when the team compared data from a July 2020 study(link is external) that reported rapid sunlight inactivation of SARS-CoV-2 in a lab setting, with a theory(link is external) of coronavirus inactivation by solar radiation that was published just a month earlier.

"The theory assumes that inactivation works by having UV-B hit the RNA of the virus, damaging it," said UC Santa Barbara mechanical engineering professor and lead author Paolo Luzzatto-Fegiz(link is external). Judging from the discrepancies between the experimental results and the predictions of the theoretical model, however, the research team felt that RNA inactivation by UV-B "might not be the whole story."

According to the letter, the experiments demonstrated virus inactivation times of about 10-20 minutes -- much faster than predicted by the theory.

"The theory predicts that inactivation should happen an order of magnitude slower," Luzzatto-Fegiz said. In the experiments, viruses in simulated saliva and exposed to UV-B lamps were inactivated more than eight times faster than would have been predicted by the theory, while those cultured in a complete growth medium before exposure to UV-B were inactivated more than three times faster than expected. To make the math of the theory fit the data, according to the letter, SARS-CoV-2 would have to exceed the highest UV-B sensitivity of any currently known virus.

Or, Luzzato-Fegiz and colleagues reasoned, there could be another mechanism at play aside from RNA inactivation by UV-B rays. For instance, UV-A, another, less energetic component of sunlight might be playing a more active role than previously thought.

"People think of UV-A as not having much of an effect, but it might be interacting with some of the molecules in the medium," he said. Those reactive intermediate molecules in turn could be interacting with the virus, hastening inactivation. It's a concept familiar to those who work in wastewater treatment and other environmental science fields.

"So, scientists don't yet know what's going on," Luzzatto-Fegiz said; "Our analysis points to the need for additional experiments to separately test the effects of specific light wavelengths and medium composition."

Results of such experiments might provide clues into new ways of managing the virus with widely available and accessible UV-A and UV-B radiation. While UV-C radiation is proved effective against SARS-CoV-2, this wavelength does not reach the earth's surface and must be manufactured. Although UV-C is presently used in air filtration and in other settings, its short wavelengths and high energy also makes UV-C the most damaging form of UV radiation, limiting its practical application and raising other safety concerns.

"UV-C is great for hospitals," said co-author Julie McMurry. "But in other environments -- for instance kitchens or subways -- UV-C would interact with the particulates to produce harmful ozone." While no single intervention will eliminate risk, this research would provide one further tool to reduce exposure, thus slowing transmission and improving health outcomes.

Co-author and UCSB mechanical engineering professor Yangying Zhu(link is external) added that UV-A turning out to be capable of inactivating the virus could be very advantageous: there are now widely available inexpensive LED bulbs that are many times stronger than natural sunlight, which could accelerate inactivation times. UV-A could potentially be used far more broadly to augment air filtration systems at relatively low risk for human health, especially in high-risk settings such as hospitals and public transportation, but the specifics of each setting warrant consideration, said co-author Fernando Temprano-Coleto.

Gustavo Aguirre and William Beltran, veterinary ophthalmologists and vision scientists at the University of Pennsylvania School of Veterinary Medicine, have studied a wide range of different retinal blinding disorders. But the one caused by mutations in the NPHP5 gene, leading to a form of Leber congenital amaurosis (LCA), is one of the most severe.

"Children with this disorder are not visual," says Aguirre. "They have a wandering, searching look on their faces and are usually diagnosed at a young age."

A nearly identical disease naturally occurs in dogs. In a new paper in the journal Molecular Therapy, Aguirre, Beltran, and colleagues at Penn and other institutions have demonstrated that a canine gene therapy can restore both normal structure and function to the retina's cone photoreceptor cells, which, in LCA patients, otherwise fail to develop normally. Delivering a normal copy of either the canine or human version of the NPHP5 gene restored vision in treated dogs.

"What's amazing is that you can take this disease in which cone cells have incompletely formed, and the therapy restores their function--they had no function whatsoever before--and recover their structure," says Aguirre.

"That plasticity is incredible and gives us a lot of hope," Beltran says.

LCA includes a wide range of inherited vision disorders characterized by blindness that strike in early childhood. The form of LCA associated with NPHP5 mutations is rare, affecting about 5,000 people worldwide. Known as a ciliopathy, it affects the cilia of cells of the retina. The cilia cells are antennalike structures on photoreceptor cells that translate the energy from light into visual signals.

In the NPHP5 disease, rod photoreceptor cells--those responsible for vision in low light--degenerate and progressively die early in the disease. Yet the cone photoreceptors, which enable color vision and, in the central retina, the perception of fine detail, while abnormal structurally, survive, albeit without function.

Aguirre and Beltran, together with colleagues and coauthors on the current work, Artur Cideciyan and Samuel Jacobson in Penn's Perelman School of Medicine, have found success with gene therapy approaches to treating a variety of inherited vision disorders. Often, they have aimed to treat early in the course of a retinal disease, before photoreceptor cells have died or entirely degenerated. But the fact that cone cells persisted in this form of LCA led the researchers to consider whether a therapy that targeted cones could not just stop but reverse the course of the disease.

Testing this approach, the team delivered retinal injections of adeno-associated viral vectors, a platform for ferrying the normal version of the NPHP5 gene, into one eye of each of nine five-week-old dogs with the vision disorder. Known as gene augmentation therapy, the injection is used to supply a healthy gene in disorders where the causative mutation leads to a defective or absent protein.

To determine the effectiveness of the treatment, the researchers used a technique called electroretinography, which measures the electrical response of photoreceptor cells to a light stimulus, as well as optical coherence tomography, which allows for the noninvasive imaging of fine cross sections of the retina. Both means of evaluating the experimental therapy rendered encouraging results. In the dogs' treated eyes, the outer segment of the cones regrew.

In addition, when the treated dogs were about six months old, their vision was tested using an obstacle-avoidance course. When their treated eye was blindfolded, they had difficulty at navigating; however, when that eye was uncovered, their ability to avoid obstacles was notably improved.

"What's so appealing and so exciting here is that we're not just stopping a disease process, we're actually reverting a photoreceptor cell that is abnormal to become normal and function," says Beltran. "This disease in dogs very closely parallels the disease in humans, in quite specific terms, so there's a lot of support for the thought that a similar treatment approach could also help children."

Ongoing studies suggest that the treatment may be effective even when delivered at later stages of disease. With further support, the researchers hope to move the research along the path to a clinical trial in people.

Cone snails aren't glamorous. They don't have svelte waistlines or jaw-dropping good looks. Yet, some of these worm-hunting gastropods are the femme fatales or lady killers of the undersea world, according to a new study conducted by an international team of researchers, including University of Utah Health scientists.

The researchers say the snails use a previously undetected set of small molecules that mimic the effects of worm pheromones to drive marine worms into a sexual frenzy, making it easier to lure them out of their hiding places so the snails can gobble them up.

"In essence, these cone snails have found a way to turn the natural sex drive of their prey into a lethal weapon," says Eric W. Schmidt, Ph.D., the study's senior author and a professor of medicinal chemistry at U of U Health. "What's exciting about this finding is that they are doing it using an interesting set of small molecules that could one day inspire the development of new types of medications to alleviate pain and other conditions."

The study appears in Science Advances.

Cone snails use a harpoon-like tooth at the end of their proboscis to inject venom into prey, instantly paralyzing them. Then, they slowly reel the immobilized animal into their mouths. For decades, scientists have been fascinated by this process. In particular, they're intrigued by the chemical makeup of various venoms the snails use to disable prey and are exploring ways to reconfigure these substances into useful human medications.

Most scientists have focused their research on cone snails that hunt fish. The venoms from these gastropods are mainly composed of tiny protein segments called peptides. These peptides can be used to develop drugs, However, because of their structural composition, they can only be used as injectable drugs and can't be taken orally.

In this new research, Schmidt and colleagues turned their attention to C. imperialis, a species of cone snail that primarily hunts Platynereis dumerili, more commonly known as a fire worm. The research team discovered that C. imperialis, or imperial cone, produces small chemicals that powerfully mimic the pheromones that trigger sexual activity in fire worms. The discovery of small molecules in the imperial cone could broaden the snail's usefulness in medical research since about 80 percent of drugs are derived from small molecules.

In laboratory experiments, one of these chemicals--called conazolium A--sparked mating behavior in female worms, causing them to swim in tight, tail-chasing circles before they released their eggs. Genuanine, a chemical akin to uric acid, had a similar effect on male fire worms, prompting them to eject their sperm.

The researchers aren't quite sure how this approach works in the wild, but they suspect that it could be a two-step process: First, the imperial cone exposes the fire worm to its fake sex pheromones, making it is easier to coax the worm out of its hiding spot (usually a coral reef). Then, like other cone snails, it harpoons the worm with a peptide-based venom to disable it.

But there's a catch: mature worms are only sexually active for a short time that coincides with a full moon.

"If you expose the worms when they are either immature or not sexually active, the mimic pheromones don't have any effect," says Joshua Torres, Ph.D., lead author of the study and a former U of U Health graduate student. "The snails have to use other hunting techniques in these incidences."

In fact, in their laboratory experiments, the researchers needed to use artificial moon light to induce sexual responses among the worms to cone snail pheromones. As a result, the researchers caution that how cone snails actually hunt in the wild and how these compounds fit into that quest remains largely unknown.

Moving forward, Schmidt and Torres are intrigued by the potential of using the small molecules produced by the imperial cone snail to lure worms out of hiding as a starting point for the development of new drugs.

Forty million people living in the Kanto region of Japan, which includes Tokyo, may be able to blame a meandering ocean current for increasing hot and humid summers, according to an analysis conducted by an international team of researchers. The Kuroshio Current flows north, bringing warm water from the tropics to Japan's southern coast. Since 2017, however, it has meandered off its traditional path, turning south before continuing north again. Now, scientists have found that the "large meander" is responsible for the uptick in humidity and temperature.

The researchers, from Tohoku University in Japan and the University of Hawaii in the United States, published their results online on Feb. 1 in the Journal of Climate, a journal of the American Meteorological Society.

"In recent years, it has become clear that the ocean influences climate," said first author Shusaku Sugimoto, associate professor of geophysics in the Graduate School of Science at Tohoku University. "Our study shows that the Kuroshio influences the regional climate - especially through the greenhouse effect of water vapor, contributing to significantly warmer temperatures."

The researchers used satellite data from the National Aeronautics and Space Administration (NASA), as well as data from the Automated Meteorological Data Acquisition System stations operated by the Japan Meteorological Agency, to examine 18 summers since 2003.

The last large meander occurred for a year from 2004 to 2005 before starting again in 2017. Controlling for other climatic events, such as storms, and considering global warming trends, the researchers assessed the differences in summers during typical summers and summers during which Kuroshio's path took a large meander.

"We found that the surface air temperature in the Kanto district increased by about 0.6 degrees Celsius as a result of the Kuroshio large meander," Sugimoto said. "As a mechanism of the warming, we discovered that the Kuroshio large meander increases evaporation and the water vapor flowing into the Kanto region, leading to a hot summer through a local greenhouse effect."

Using Thom's index, a widely used standard of human discomfort based on temperature and humidity, the team found large meander summers resulted in 13.1 days of most people experiencing discomfort. That's a 160% increase over the 8.1 discomfort days of non-large meander summers.

"This is a result that affects the lives of many people," Sugimoto said. "Our analysis showed the Kuroshio path state is responsible for the climatic comfort of living in Tokyo, Japan, and our approach is also applicable in other coastal cities worldwide."

The researchers plan to apply their work to improve both climate and local weather forecasts, according to Sugimoto, so that people may be better prepared to handle higher temperatures and more humidity.

"The results of this research are expected to contribute to the reduction of heatstroke risk and the formulation of climate change adaptation plans," Sugimoto said. "This finding detects the influence of the ocean on regional climate, and we hope that it will contribute to the improvement of weather and seasonal forecasts."

WASHINGTON, March 30, 2021 -- As ethanol, biodiesel, and other biofuels continue to present challenges, such as competing with food security or lacking the technology for more efficient and low-cost production, microalgae are gaining momentum as a biofuel energy crop.

In their paper, published in the Journal of Renewable and Sustainable Energy, by AIP Publishing, Yangzhou University researchers in China show how a combination of monochromatic red and blue LED illumination on one type of microalga can enhance its growth and increase the biosynthesis of critical components, such as lipids, for microalgae feedstock development.

The researchers focused on Dunaliella salina (D. salina), typically extracted from sea salt fields and found in salt lakes. Easily cultivated and known for its bright pink color because of its high levels of carotenoid, D. salina is widely used in foods and cosmetics.

Microalgae tend to accumulate higher amounts of lipids (fatty acids that make up natural oils and waxes) than other biomass feedstocks do, which means a much higher percentage of the organisms can be turned into usable biofuel. In the case of D. salina, the lack of a cell wall could make algae biofuel production easier to pursue.

LEDs, as tunable single-color light sources, are already used to optimize plant growth, particularly in greenhouse cultivation. All parts of the visible spectrum are used in photosynthesis, but light also influences plant development. Adding more blue or red light, for instance, affects different plants in different ways. Optimal illumination conditions for microalgae growth and lipid production yield remain unknown.

In their study, the researchers applied red, blue, or combined red-blue illumination to D. salina culture. They found different intensities of blue light did not significantly enhance microalgae growth but boosted the lipid, protein, and carbohydrate levels. Red light, on the other hand, reduced algae growth and lipid formation, compared to blue and white light.

However, when red and blue lights were simultaneously applied in various ratios, the microalgae showed a major boost in growth and lipid productivity. The optimal 4-to-3 ratio of red and blue light significantly improved lipid productivity by more than 35% and increased dry biomass yield by more than 10% compared to the white light control.

The researchers are planning to analyze the composition of fatty acids synthesized in the algae under the favorable combined lighting for increased lipid production.

"Biodiesel performance is dependent on the composition of fatty acids, so we want to determine how the combined monochromatic lights would affect the quality of microalgae biodiesel," author Xiaojian Zhou said.

WASHINGTON, March 30, 2021 -- Scientists are developing tools to observe the biological machinery in in vivo animal models to be able to understand and better treat severe brain diseases like Alzheimer's disease and many other conditions. Holographic endoscopes attracted researchers' interest because of their potential to conduct minimally invasive observations inside the human body.

These tools can shed light on the biological processes occurring at the macromolecular and subcellular levels, which usually remain hidden from sight as most tissue is opaque to visible radiation. In APL Photonics, by AIP Publishing, researchers from the Leibniz Institute of Photonic Technology in Germany created a particularly narrow endoscope made of single hair-thin optical fibers that uses holographic methods to reconstruct images of macroscopic objects placed in front of the far end of the endoscope.

"We were positively surprised that the imaging quality was well-maintained at larger imaging distances, even for objects placed at a half meter from the endoscope," said author Ivo Leite. "We expected that the low number of photons collected in this range would give rise to much higher detection noise."

Efforts in imaging through multimode-fiber endoscopes previously focused on working distances typically smaller than 20 micrometers to resolve micrometer-scale details. This limits the field of view to the size of the fiber core.

The researchers brought the imaging operation to the observation of macroscopic objects, which can be placed far away from the endoscope. Researchers increased the imaging performance in terms of image definition to 100,000 pixels per image frame, an order of magnitude larger than previous holographic endoscopes and reaching the definition of modern video endoscopes.

Their efforts pave the way for bringing this class of minimally invasive endoscopes to clinical applications. The macroscopic imaging modality shown in this study will be essential to analyze biological samples at the tissue scale -- just as conventional clinical endoscopes do -- as well as to guide the instrument insertion.

Once a region of interest is identified, the hologram sequence displayed by the spatial light modulator can be updated to switch the imaging modality and perform observations at the cellular and subcellular levels.

"The potential for such flexibility in imaging operation through the same unmodified endoscope is a unique feature that, we believe, holographic endoscopes could soon offer," said author Tomas Cizmar.

The researchers' light control methods could be used to deliver practically any type of photonics tool through a hair-thin endoscope, which could have applications in a range of areas, such as optical transfection, subcellular laser surgery, and laser-assisted microfabrication.

It makes evolutionary sense for long-lived animals to have complex social relationships - such as friends and enemies - researchers say.

Some species and individuals focus their energy on reproduction (live fast, die young), while "slow-living" animals prioritise survival and tend to live longer lives.

In the new paper, University of Exeter scientists argue that natural selection favours complex social structures among slow-living animals - meaning that knowing their friends and enemies is easier for animals with longer lifespans, and helps them live even longer.

Meanwhile, fast-lived species should only bother with such social relationships if it increases their chances of reproduction.

"Slow-living species can afford to invest in social relationships, as they live long enough to enjoy the pay-offs," said Professor Dave Hodgson, Director of the Centre for Ecology and Conservation on Exeter's Penryn Campus in Cornwall.

"There is strong evidence that strong social bonds are beneficial for survival in slow-living species, including humans.

"We suggest there is a 'positive feedback' - certain social behaviours lead to a longer life, and longer lifespan promotes the development of social bonds."

Professor Hodgson said there is "growing evidence" that differentiated social relationships have a bigger positive effect on survival than on reproduction.

As a result, fast-lived species do not gain the same evolutionary advantages from social relationships as slow-lived species.

Examples of fast-living species could include shrews and crickets, while animals such as mongooses, badgers and hyenas, and indeed humans, have a slower "pace of life".

Pace of life measurements take body size into account. Larger animals tend to live longer, but pace of life can vary significantly in two species of similar size.

Dr Matthew Silk, also of the University of Exeter, said: "If we want to understand more about social relationships and lifespan, we need to think about the relationship between the two.

"More research is needed to explore the social structures of wild animals.

"This could help us understand the links between social bonds, survival and reproduction."

Professor Hodgson said: "Our proposal, that strong and weak social bonds will be more prevalent in slower-living animals, is theoretical.

"We know a lot about animal lifespans, but we know too little about the social structures of many types of animal.

"If we are right, then social bonds could really be key to longer life."

One in four Germans suffers from metabolic syndrome. Several of four diseases of affluence occur at the same time in this 'deadly quartet': obesity, high blood pressure, lipid metabolism disorder and diabetes mellitus. Each of these is a risk factor for severe cardiovascular conditions, such as heart attack and stroke. Treatment aims to help patients lose weight and normalise their lipid and carbohydrate metabolism and blood pressure. In addition to exercise, doctors prescribe a low-calorie and healthy diet. Medication is often also required. However, it is not fully clear what effects nutrition has on the microbiome, immune system and health.

A research group led by Dr Sofia Forslund and Professor Dominik N. Müller from the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the Experimental and Clinical Research Center (ECRC) has now examined the effect a change of diet has on people with metabolic syndrome. The ECRC is jointly run by the MDC and Charité Universitätsmedizin Berlin. "Switching to a healthy diet has a positive effect on blood pressure," says Andras Maifeld, summarising the results. "If the diet is preceded by a fast, this effect is intensified." Maifeld is the first author of the paper, which was recently published in the journal "Nature Communications".

Broccoli over roast beef

Dr Andreas Michalsen, Senior Consultant of the Naturopathy Department at Immanuel Hospital Berlin and Endowed Chair of Clinical Naturopathy at the Institute for Social Medicine, Epidemiology and Health Economics at Charité - Universitätsmedizin Berlin, and Professor Gustav J. Dobos, Chair of Naturopathy and Integrative Medicine at the University of Duisburg-Essen, recruited 71 volunteers with metabolic syndrome and raised systolic blood pressure. The researchers divided them into two groups at random.

Both groups followed the DASH (Dietary Approach to Stop Hypertension) diet for three months, which is designed to combat high blood pressure. This Mediterranean-style diet includes lots of fruit and vegetables, wholemeal products, nuts and pulses, fish and lean white meat. One of the two groups did not consume any solid food at all for five days before starting the DASH diet.

On the basis of immunophenotyping, the scientists observed how the immune cells of the volunteers changed when they altered their diet. "The innate immune system remains stable during the fast, whereas the adaptive immune system shuts down," explains Maifeld. During this process, the number of proinflammatory T cells drops, while regulatory T cells multiply.

A Mediterranean diet is good, but to also fast is better

The researchers used stool samples to examine the effects of the fast on the gut microbiome. Gut bacteria work in close contact with the immune system. Some strains of bacteria metabolise dietary fibre into anti-inflammatory short-chain fatty acids that benefit the immune system. The composition of the gut bacteria ecosystem changes drastically during fasting. Health-promoting bacteria that help to reduce blood pressure multiply. Some of these changes remain even after resumption of food intake. The following is particularly noteworthy: "Body mass index, blood pressure and the need for antihypertensive medication remained lower in the long term among volunteers who started the healthy diet with a five-day fast," explains Dominik Müller. Blood pressure normally shoots back up again when even one antihypertensive tablet is forgotten.

Blood pressure remains lower in the long term - even three months after fasting

Together with scientists from the Helmholtz Centre for Infection Research and McGill University, Montreal, Canada, Forslund's working group conducted a statistical evaluation of these results using artificial intelligence to ensure that this positive effect was actually attributable to the fast and not to the medication that the volunteers were taking. They used methods from a previous study in which they had examined the influence of antihypertensive medication on the microbiome. "We were able to isolate the influence of the medication and observe that whether someone responds well to a change of diet or not depends on the individual immune response and the gut microbiome," says Forslund.

If a high-fibre, low-fat diet fails to deliver results, it is possible that there are insufficient gut bacteria in the gut microbiome that metabolise fibre into protective fatty acids. "Those who have this problem often feel that it is not worth the effort and go back to their old habits," explains the scientist. It is therefore a good idea to combine a diet with a fast. "Fasting acts as a catalyst for protective microorganisms in the gut. Health clearly improves very quickly and patients can cut back on their medication or even often stop taking tablets altogether." This could motivate them to stick to a healthy lifestyle in the long term.

Artificial Intelligence is now capable of generating novel, functionally active proteins, thanks to recently published work by researchers from Chalmers University of Technology, Sweden.

"What we are now able to demonstrate offers fantastic potential for a number of future applications, such as faster and more cost-efficient development of protein-based drugs," says Aleksej Zelezniak, Associate Professor at the Department of Biology and Biological Engineering at Chalmers.

Proteins are large, complex molecules that play a crucial role in all living cells, building, modifying, and breaking down other molecules naturally inside our cells. They are also widely used in industrial processes and products, and in our daily lives.

Protein-based drugs are very common - the diabetes drug insulin is one of the most prescribed. Some of the most expensive and effective cancer medicines are also protein-based, as well as the antibody formulas currently being used to treat COVID-19.

From computer design to working proteins in just a few weeks

Current methods used for protein engineering rely on introducing random mutations to protein sequences. However, with each additional random mutation introduced, the protein activity declines.

"Consequently, one must perform multiple rounds of very expensive and time-consuming experiments, screening millions of variants, to engineer proteins and enzymes that end up being significantly different from those found in nature," says research leader Aleksej Zelezniak, continuing:

"This engineering process is very slow, but now we have an AI-based method where we can go from computer design to working protein in just a few weeks."

The new results from the Chalmers researchers were recently published in the journal Nature Machine Intelligence and represent a breakthrough in the field of synthetic proteins. Aleksej Zelezniak's research group and collaborators have developed an AI-based approach called ProteinGAN, which uses a generative deep learning approach.

In essence, the AI is provided with a large amount of data from well-studied proteins; it studies this data and attempts to create new proteins based on it.

At the same time, another part of the AI tries to figure out if the synthetic proteins are fake or not. The proteins are sent back and forth in the system until the AI cannot tell apart natural and synthetic proteins anymore.

This method is well known for creating photos and videos of people who do not exist, but in this study, it was used for producing highly diverse protein variants with naturalistic-like physical properties that could be tested for their functions.

The proteins widely used in everyday products are not always entirely natural but are made through synthetic biology and protein engineering techniques. Using these techniques, the original protein sequences are modified in the hope of creating synthetic novel protein variants that are more efficient, stable, and tailored towards particular applications. The new AI-based approach is of importance for developing efficient industrial enzymes as well as new protein-based therapies, such as antibodies and vaccines.

A cost-efficient and sustainable model

Assistant Professor Martin Engqvist, also of the Department of Biology and Biological Engineering, was involved in designing the experiments to test the AI synthesised proteins.

"Accelerating the rate at which we engineer proteins is very important for driving down development costs for enzyme catalysts. This is the key for realising environmentally sustainable industrial processes and consumer products, and our AI model, as well as future models, will enable that. Our work is a vital contribution in that context" says Martin Engqvist.

"This kind of work is only possible in the type of multidisciplinary environment that exists at our Division - at the interface of computer science and biology. We have perfect conditions to experimentally test the properties of these AI-designed proteins," says Aleksej Zelezniak.

The next step for the researchers is to explore how the technology could be used for specific improvements to protein properties, such as increased stability, something which could have great benefit for proteins used in industrial technology.

The latest gene editing technology, prime editing, expands the "genetic toolbox" for more precisely creating disease models and correcting genetic problems, scientists say.

In only the second published study of prime editing's use in a mouse model, Medical College of Georgia scientists report prime editing and traditional CRISPR both successfully shut down a gene involved in the differentiation of smooth muscle cells, which help give strength and movement to organs and blood vessels.

However, prime editing snips only a single strand of the double-stranded DNA. CRISPR makes double-strand cuts, which can be lethal to cells, and produces unintended edits at both the work site as well as randomly across the genome, says Dr. Joseph Miano, genome editor, molecular biologist and J. Harold Harrison, MD, Distinguished University Chair in Vascular Biology at the MCG Vascular Biology Center.

"It's actually less complicated and more precise than traditional CRISPR," Miano says of prime editing, which literally has fewer components than the game-changing gene-editing tool CRISPR.

Miano was among the first wave of scientists to use CRISPR to alter the mouse genome in 2013. Two scientists were awarded the 2020 Nobel Prize in Chemistry for the now 9-year-old CRISPR, which enabled rapid development of animal models, as well as the potential to cure genetic diseases like sickle cell, and potentially reduce the destruction caused by diseases like cancer, in which environmental and genetic factors are both at play.

Prime editing is the latest gene-editing technology, and the MCG scientists report in the journal Genome Biology that they were able to use it to remove expression of a gene in smooth muscle tissue, illustrating prime editing's ability to create cell-specific knockout mice without extensive breeding efforts that may not result in an exact model, says Dr. Xiaochun Long, molecular biologist in the Vascular Biology Center. Miano and Long are corresponding authors of the new study.

Long, Miano and their colleagues did a comparative study using traditional CRISPR and prime editing in the gene Tspan2, or tetraspan-2, a protein found on the surface of cells. Long had earlier found Tspan2 was the most prominent protein in smooth muscle cell differentiation and was likely mutated in cardiovascular disease. She also had identified the regulatory region of this gene in cultured cells. However, it was unclear whether this regulatory region was important in mice.

They used CRISPR to create a subtle change in a snippet of DNA within the promoter region of Tspan2, in this case a three-base change, their standard approach to inactivating control regions of genes. DNA has four base pairs -- adenine, cytosine, guanine and thymine -- which pair up in endless different combinations to make us, and which gene-editing tools alter.

CRISPR created a double-strand break in the DNA and following the three-base change, the Tspan2 gene was no longer turned on in the aorta and bladder of mice.

They then used prime editing to make a single-strand break, or nick, and a single-base change -- like most of the gene mutations that occur in our body -- and found this subtle change also turned the Tspan2 gene off in the aorta and bladder, but without the collateral damage of CRISPR.

"We were trying to model what could happen with a single nucleotide change," says Miano. "We asked the question if we incorporate a single-base substitution, if we just make one base change, what happens to Tspan2 expression? The answer is it did the same thing as the traditional CRISPR editing: It killed the gene's expression."

But there were also important differences. Using CRISPR, they found evidence of significant "indels," short for insertions or deletions of bases in genes, which were unintended, both near the site where the intended edit was made and elsewhere.

The published paper includes a chart with numerous black bars illustrating where multiple nucleotides, the building blocks of DNA and RNA, are gone after using CRISPR. Indels are those unintended changes that genome editors strive to avoid because they can create deficits in gene expression and possible disease. With off-targeting, you could end up substituting one disease for another, Miano says.

But with prime editing, they saw essentially no indels either at the Tspan2 promoter region or elsewhere.

A Manhattan plot illustrated the off-targeting across all chromosomes using both techniques, with the CRISPR skyline stacking up like a real city while the prime editing skyline is comparatively flat.

"Prime editing is a less intrusive cut of the DNA. It's very clean," Miano says. "This is what we want: No detectable indels, no collateral damage. The bottom line is that unintended consequences are much less and it's actually less complicated to use."

Traditional CRISPR has three components, the molecular scissors, Cas9, the guide RNA that takes those scissors to the precise location on DNA and a repair template to fix the problem. Traditional CRISPR cuts both strands of the DNA, which also can happen in nature, can be catastrophic to the cell and must be quickly mended.

Prime editing has two arms, with a modified Cas9, called a Cas9 nickase, that will only make a single-strand cut. The scissors form a complex called the "prime editor" with a reverse transcriptase, an enzyme that can use an RNA template to produce a piece of DNA to replace the problematic piece in the case of a disease-causing mutation. PegRNA, or prime editing guide RNA, provides that RNA template, gets the prime editor where it needs to work and helps stabilize the DNA strands, which are used to being part of a couple.

During the repair of the nicked strand of targeted DNA, the prime editor "copies" a portion of the pegRNA containing the programmed edit, in this case a single-base substitution, so that the repaired strand will now carry the single base edit. In the case of creating a disease model, that enables scientists to "bias" the repair so the desired mutation is created, Miano says.

Dr. David Liu, chemical biologist, Richard Merkin Professor and director of the Merkin Institute of Transformative Technologies in Healthcare at Harvard University and the Massachusetts Institute of Technology, and his colleagues developed the first major gene editing technology to follow CRISPR. They reported on base editing technology in 2016, which uses "base editors" Liu described as "pencils, capable of directly rewriting one DNA letter into another by actually rearranging the atoms of one DNA base to instead become a different base." Liu and his postdoctoral fellow Dr. Andrew Anzalone, first reported on prime editing in the journal Nature in October 2019. Liu is a coauthor on the newly published study in Genome Biology on prime editing in mice.

Liu's original work on prime editing was done in culture, and others have shown its efficacy in plants. This is more proof of principle, Miano says.

The MCG scientists hope more of their colleagues will start using prime editing in their favorite genes to build experience and hasten movement toward its use in humans.

Their long-term goals including using safe, specific gene editing to correct genetic abnormalities during human development that are known to result in devastating malformations and disease like heart defects that require multiple major surgeries to correct.

Allison Yang, senior research assistant in the Miano lab, is preparing to use prime editing to do an in utero correction of the rare and lethal megacystis-microcolon-intestinal hypoperistalsis syndrome, which affects muscles of the bladder and intestines so you have difficulty moving food through the GI tract and emptying the bladder. In early work with CRISPR on vascular smooth muscle cells, Miano and colleagues inadvertently created a near-perfect mouse model of this human disease that can kill babies.

HANOVER, N.H. - March 30, 2021 - Cyanobacteria living at the bottom of lakes may hold important, under-researched clues about the threat posed by these harmful organisms, according to a Dartmouth-led study.

The research, published in the Journal of Plankton Research, urges a more comprehensive approach to cyanobacteria studies in order to manage the dangerous blooms during a time of global climate change.

"Most studies of cyanobacteria focus on the times when they are visible in the water column," said Kathryn Cottingham, the Dartmouth Professor in the Arts and Sciences, and a professor of biology. "By concentrating on this part of the life cycle, we may be missing important clues about how these harmful organisms are responding to ongoing global change."

Also known as blue-green algae, blooms of cyanobacteria are increasing in many freshwater systems worldwide, damaging the quality of lake water and affecting lake communities. The blooms also threaten human health through toxins that can damage organ systems.

Cyanobacteria are complex, but researchers are bringing together clues on how they respond to changing seasons.

Freshwater cyanobacteria live either suspended in the water column or at the lake bottom depending, in part, on water temperature. During warmer months, suspended "pelagic" cyanobacteria thrive in warm, well-lit surface waters. In the fall, they sink to the bottom and spend the winter in a resting or fully dormant state.

The Dartmouth-led study focuses on how cyanobacteria behave around the bottom-dwelling "overwinter" period. The research stresses that the sediment-dwelling stage returns to the water column with higher water temperatures, often following the mixing of the water column. Climate change is decreasing some types of mixing but increasing others - such as that caused by extreme precipitation events.

According to the paper, if mixing is constrained and cyanobacteria are left at the bottom, blooms could decrease. "A more complete understanding of all stages of the cyanobacterial life cycle will enable plankton researchers to better predict how ongoing climate change will affect the frequency, intensity and duration of cyanobacterial blooms," the study said.

Land-use changes--such as deforestation, fertilizer use, and development--and climate change are considered the main drivers of cyanobacteria outbreaks. Although the precise causes of the blooms are still being studied, researchers believe that they come from ongoing increases in nutrient loading, temperature and precipitation.

"Our work indicates that cyanobacterial blooms could either increase or decrease as a result of climate change, necessitating preventative lake management to limit human health risks," said Cayelan Carey, associate professor of biological sciences at Virginia Tech and co-author on the study. "Avoiding fertilizer use and installing waterfront buffers can help decrease cyanobacteria, thereby providing 'insurance' against potential cyanobacteria increases due to warmer temperatures in the future."

The study focused on temperate lakes, but the research team stresses that other waterbodies should be include in the proposed research agenda.

Kathleen Weathers from the Cary Institute, and Holly Ewing and Meredith Greer from Bates College also contributed to the study.

As our planet warms, seas rise and catastrophic weather events become more frequent, action on climate change has never been more important. But how do you convince people who still don't believe that humans contribute to the warming climate?

New UBC research may offer some insight, examining biases towards climate information and offering tools to overcome these and communicate climate change more effectively.

Researchers examined 44 studies conducted over the past five years on the attentional and perceptual biases of climate change - the tendency to pay special attention to or perceive particular aspects of climate change. They identified a number of differences between people of different political orientations, finding that those who were more liberal tended to pay attention to the rising part of a global temperature graph. When the temperature increase was emphasized in red, these people were more likely to take actions on climate change, including signing petitions and donating money. Not so for conservatives, where this effect was absent.

The review explains cognitive reasons for a lack of actions on climate change, says Prof. Jiaying Zhao (she/her/hers), a Language Sciences member and senior author, along with her student Yu Luo (he/him/his). "Climate change is a problem of collective behaviours so to address it, you have to address behaviours first."

These biases include that liberals who were concerned about the climate were more accurate at identifying climate-related words (e.g., carbon) than neutral words (e.g., coffee) in a rapid visual presentation, while conservatives who weren't concerned were no better at seeing climate-related words over neutral words, suggesting that people with different political orientations show different attentional priorities to climate change information.

This is something with which Prof. Zhao, an associate professor in the department of psychology and the Institute for Resources, Environment and Sustainability, has personal experience. "Anything to do with climate change in the news catches my attention. Anything about the climate in the headlines - carbon, flooding, hurricanes - it draws my attention quickly." Everyone has biases, Prof. Zhao says, and she is working to correct her own, "but no one is immune." Indeed, the review noted people with higher numeracy or literacy skills are better at selectively analyzing information to confirm their prior beliefs.

Perceptual biases were highlighted as well: the review concluded that misperceptions of norms within a group can be a barrier to bipartisan climate policy making in the U.S., with one study showing that people often hold distorted perceptions of the degree of opposition from those outside their group, resulting in a false sense of polarization. Another study found that the perception of greenhouse gas emissions was often incorrect, with people not understanding how global warming works, or the emissions associated with things like a hamburger or a flight.

Prof. Zhao stresses the urgency of addressing these biases to spur actions on climate change. "It is an increasingly urgent global challenge and we need to do something about it fast." The authors suggest several communication tools to do so, including that communication of climate change should align with a target group's ideologies and values: for conservatives, this could include framing pro-environmental actions as benefiting the economy, building a more moral and caring community or benefiting future generations. Negative framing has been shown to be more effective, Prof. Zhao says, so pointing out the negative consequences to one's family of climate change could be an effective communication tool. "Regardless of your political orientation, if it's going to harm your children, every parent will want to take action."

Other tools include providing accurate information on social norms for both in-groups and out-groups, for instance, the actual percentage of conservatives who do not believe in anthropogenic climate change; and providing simple and understandable visualizations of the greenhouse gas emissions of individual actions and items.

Whichever communication tool is used, the authors advise targeting specific cognitive processes associated with the audience group to effectively persuade people. And further work is needed on how to translate information to personal action, they say. But the time to act is now, says Prof. Zhao, with the paper providing policy makers clues to, and solutions for, inaction. "I see an urgent need to call for collective climate actions. We're not doing enough to address climate change and this paper explains some of the reasons."

In a new study published in the Cell Research, Chen-Yu Zhang's group at Nanjing University reports "In vivo self-assembled small RNA is the new generation of RNAi therapeutics".

The development of RNAi therapy has undergone two major stages, direct injection of synthetic siRNAs and delivery with artificial vehicles; both have not realized the full therapeutic potential of RNAi in clinic. In this study, Chen-Yu Zhang's group reprogram host liver with genetic circuits to direct the synthesis and self-assembly of siRNAs into secretory exosomes. In vivo assembled siRNAs are systematically distributed to multiple tissues or targeted to specific tissues (e.g., brain), inducing potent target gene silencing in these tissues. The therapeutic value of this strategy is demonstrated in a variety of diseases ranging from cancers to metabolic diseases. Overall, in vivo self-assembled siRNA represents a next generation RNAi therapeutics, which makes RNAi therapy feasible.

The scientific significance of these findings is highlighted below:

The lack of a safe and efficient in vivo delivery system remains a major obstacle to the clinical translation of RNAi therapy. This study reprograms the native circulating exosome system of mammals with artificial genetic circuits to facilitate the transfer of siRNA in vivo. This strategy re-conceptualizes delivery vehicles as "medicines" instead of "agents", thus avoiding the safety and efficiency concerns associated with conventional delivery techniques.

Most human diseases are caused by the mutation or dysfunction of multiple genes. The design of in vivo self-assembled siRNAs offers the co-expression of tandem siRNAs and simultaneous silencing of multiple genes in vivo (e.g. EGFR and TNC in glioma), thus allowing precise control of gene expression in a purpose-driven mode.

Since in vivo self-assembled siRNAs are delivered by circulating exosomes, specific tissue targeting may be achieved by the co-expression of tissue-specific protein tags on exosome membrane. Thus, in vivo self-assembled siRNAs can be directed to specific tissues, especially for those with biological barriers (e.g., blood-brain-barrier).

This study is the first attempt to combine genetic circuits with native exosome circulating system to achieve gene silencing in vivo. Self-assembled siRNAs may be a novel gene silencing tool for studying gene function in vivo.

The comparison of this strategy with conventional siRNA delivery methods are summarized below:

Synthetic siRNAs:

delivery strategy: [naked/chemically modified siRNAs]

pros: [easy to produce]

cons: [rapidly degraded in circulation(50 mg/kg, half-life of 95 minutes); hard to enter cells]

cost: [$92,500/dose (5 mg/kg)]

Artificial vehicles:

delivery strategy: [lipid nanoparticles/cationic polymers]

pros: [easy to produce, stable, easy to enter cells]

cons: [immunogenic, enter lysosomes]

cost: [$28,100/dose (0.3 mg/kg)]

delivery strategy: [viruses]

pros: [easy to produce, long-term expression]

cons: [immunogenic, activate oncogenes]

cost: [$356,000/dose]

delivery strategy: [in vitro assembled exosomes]

pros: [immune-compatible, high delivery efficiency]

cons: [hard to produce, difficult to apply quality control]

cost: [$32,700/dose]

In vivo self-assembled siRNAs

delivery strategy: [self-assembled in liver and transferred via endogenous exosomes]

pros: [immune-compatible, high delivery efficiency (5 mg/kg, half-life of more than 12 hours), easy to produce, controllable, target any gene in any tissue]

cost: [$4,680/dose (5 mg/kg)]

"With these findings", Chen-Yu Zhang added, "we believe that this study is very important for addressing the urgent topics in biomedicine and will be of broad interest to biomedical researchers and pharmaceutical industries".

Failure to comply with international exposure recommendations for air pollution, noise, heat and access to green space is associated with more than 1,000 deaths per year in Barcelona and more than 900 in Madrid, accounting for 7% and 3% of overall premature mortality, respectively.

This is the conclusion of a new study by the Barcelona Institute for Global Health (ISGlobal), a centre supported by the "la Caixa" Foundation. This study is the first to estimate premature mortality impacts and the distribution by socioeconomic status of multiple environmental exposures related to urban planning and transport in the two cities.

Today, more than half of the global population lives in cities. In Spain, this trend is even more pronounced, with 80% of the population living in urban areas. Madrid and Barcelona are two of Europe's most populous cities, and they also have some of the highest rates of socioeconomic inequality among inhabitants. Recent studies in European cities such as Vienna, Bradford and Barcelona have shown that a considerable proportion of the premature mortality burden--between 8% and 20%--is associated with poor urban and transport planning.

The new study, published in Environmental Research, estimated the impact of non-compliance with international exposure level recommendations for air pollution--fine particulate matter (PM2.5) and nitrogen dioxide (NO2)--as well as excess heat, traffic noise and lack of green space on residents over 20 years of age in Barcelona and Madrid, cities with different urban planning practices. Whereas Madrid is structured around a central nucleus where most economic activity is concentrated, Barcelona is a compact city whose economic activity is distributed across different neighbourhoods.

The study focused on identifying environmental inequities. "Our goal was to identify the population groups that were most exposed and most vulnerable to the effects of poor urban and transport planning," commented ISGlobal researcher Tamara Iungman, lead author of the study.
As for methodology, the researchers used a tool called Urban and Transport Planning Health Impact Assessment (UTOPHIA), which was developed by a team at ISGlobal. "We compared current exposure levels with international recommendations and estimated the fraction of preventable premature deaths that could be avoided if we were to comply with those recommendations," explained Iungman.

Attributable Deaths

The findings showed that non-compliance with WHO's exposure recommendations for air pollution, noise, and access to green space, along with excess heat, were associated with 1,037 premature deaths per year in Barcelona (1). Fine particulate air pollution was the exposure associated with the highest premature mortality, accounting for 524 deaths per year (48% of total attributable deaths), followed by lack of green space (277 deaths), exposure to traffic noise (124 deaths), heat (112 deaths) and exposure to NO2 (12 deaths).

For Madrid, the total number of deaths attributable to non-compliance with international recommendations was 902. Lack of green space was the exposure associated with the highest premature mortality (337 deaths per year), followed by excessive heat (244 deaths), NO2 air pollution (207 deaths), PM2.5 air pollution (173 deaths) and noise (148 deaths).

An earlier ISGlobal study attributed 20% of premature mortality in Barcelona to poor urban and transport planning. "The lower values obtained in this health impact assessment of Barcelona and Madrid--7.1% and 3.4%, respectively--could be attributed to the fact that physical activity was not included in this study, in addition to improvements in adverse exposure levels in recent years, as well as the different methodology used to estimate the mortality attributable to noise," commented Iungman.

Differences Between Barcelona and Madrid

With better urban and transport planning, Barcelona could avoid nearly twice as many deaths as Madrid: 72 versus 33 deaths per 100,000 inhabitants. "This difference can be partly explained by the fact that the scientific evidence associates higher mortality with exposure to PM2.5, which is higher in Barcelona; another explanation would be the greater traffic and population density in Barcelona than in Madrid, given that its area represents 1/6th of Madrid's", explained ISGlobal researcher Natalie Mueller, coordinator of the study.

With an annual average of 15 μg/m3, Barcelona exceeded the maximum level recommended by the World Health Organisation (WHO) for PM2.5 (10 μg/m3). For NO2 levels, however, the city's annual average of 37 μg/m3 was under the recommended maximum of 40 μg/m3. Madrid exceeded the WHO recommendations on both counts, with an annual average of 11 μg/m3 for PM2.5 and 42 μg/m3 for NO2.

The main difference between the two cities was in air pollutants. The findings showed higher levels of fine particulate matter in Barcelona and NO2 in Madrid, as well as different spatial distributions: high levels of PM2.5 throughout Barcelona and higher levels of NO2 in the centre of the Spanish capital. "While the main source of NO2 emissions is local motor-vehicle traffic, fine particulate matter has a higher dispersion capacity and is also associated with other combustion sources besides traffic," commented Mueller. "The port and the large industrial areas near Barcelona could influence the high levels of fine particulate matter in the city."

As for green space, the vast majority of the population in Madrid and Barcelona--84% and 95%, respectively--did not have adequate access to these natural environments according to the standards of the WHO, which recommends that people should live within 300 metres of a green space measuring at least half a hectare. This widespread lack of access to green space shows that "in order for green spaces to have health benefits--in addition to mitigating other exposures such as noise and excess heat--it is necessary to consider not only their availability in the city, but also their distribution so that residents can access them on foot," commented Mueller.

With regard to noise, 97% of the population of Madrid and 96% of the population of Barcelona were exposed to traffic noise levels higher than the WHO's recommended values. "Both cities had a considerable mortality burden attributable to traffic noise, which underscores how important it is to reduce noise to improve the health of the population," argued Mueller.

Although there are no specific guidelines for heat, the researchers calculated the temperature corresponding to the smallest number of heat-related deaths in each city: 22.5°C for Barcelona and 21.5°C for Madrid and estimated the impacts of a potential reduction of 1º. "The two cities had similar attributable mortality rates and we found correlations between less green space and higher levels of heat and noise," added Iungman.

Environmental Inequities

The findings show that poor urban and transport planning in Barcelona is associated with higher mortality in census tracts with lower socioeconomic status, whereas in Madrid the attributable mortality burden varied by environmental exposure. Although air pollution, lack of green space and excessive heat are widespread problems in Barcelona, attributable mortality rates were overall higher in the most deprived areas. Thus, populations in the most deprived census tracts had a mortality risk 1.26 times higher than that of the least deprived groups, probably because of an already higher underlying vulnerability.

In Madrid, the most deprived neighbourhoods had higher exposure to PM2.5 and heat than the least deprived neighbourhoods, while the inverse was true for NO2 and noise. This is probably due to the fact that lower socioeconomic population subgroups reside more peripheral and closer to industrial areas, where the cost of living is cheaper -and thus they are more exposed to PM2.5 and heat-, while middle and upper middle socioeconomic population reside in Madrid highly trafficked city center, with greater exposure to NO2 and traffic noise. With respect to green spaces, lack of access affected people of both low and middle socioeconomic status. This pattern was also reflected in its attributable mortality, where only the least deprived areas were the ones having less adverse impacts, probably due to lower underlying vulnerability and better general health status.

Co-author Mark Nieuwenhuijsen, Director of the Urban Planning, Environment and Health Initiative at ISGlobal, commented: "This analysis is in line with previous research showing that people living in more deprived neighbourhoods tend to be more exposed to harmful environmental exposures compared to those living in wealthier areas, although this inequity varies according to the design characteristics and historical development of each city."

"This study shows that environmental exposures have a large impact on premature mortality and underscores the importance of designing cities with health impacts in mind, valuing the specificities of each urban environment and prioritising disadvantaged populations," concluded Nieuwenhuijsen. "Health impact assessments are a powerful tool for guiding policymakers towards cities that are healthy, sustainable and fair for all residents."

In modern basic life science research as well as in drug discovery, recording and analyzing the images of cells over time using 3D microscopy has become extremely important. Once the images have been recorded, the same cell in different images at different time points has to be accurately identified ("cell tracking") because the living cells captured in the images are in motion. However, tracking many cells automatically in 3D microscope videos has been considerably difficult.

In the Kimura laboratory at the Nagoya City University, Dr. Chentao Wen and colleagues developed the 1st AI-based software called 3DeeCellTracker that can run on a desktop PC and automatically track cells in 3D microscope videos. Using the software, they were able to measure and analyze the activities of ~100 cells in the brain of a moving microscopic worm, in a naturally beating heart of a young small fish, and ~1000 cancer cells cultured in 3D under laboratory conditions, which were recorded with different types of cutting-edge microscope systems.

This versatile software can now be used across biology, medical research, and drug development to help monitor cell activities.