Culture

Coronaviruses like the one that causes COVID-19 are studded with protein "spikes" that bind with receptors on the cells of their victims ­- the first step in infection. Now scientists have made the first detailed images of those spikes in their natural state, while still attached to the virus and without using chemical fixatives that might distort their shape.

They say their method, which combines cryogenic electron microscopy (cryo-EM) and computation, should produce quicker and more realistic snapshots of the infection apparatus in various strains of coronavirus, a critical step in designing therapeutic drugs and vaccines.

"The advantage of doing it this way is that when you purify a spike protein and study it in isolation, you lose important biological context: How does it look in an intact virus particle? It could possibly have a different structure there," said Wah Chiu, a professor at DOE's SLAC National Accelerator Laboratory and Stanford University and senior author of the study. They described their results in Quarterly Reviews Biophysics Discovery.

Seven strains of coronaviruses are known to infect humans. Four cause relatively mild illnesses; the other three - including SARS-CoV-2, the virus that causes COVID-19 - can be deadly, said co-author Jing Jin, an expert in the molecular biology of viruses at Vitalant Research Institute in San Francisco. Scientists at Vitalant hunt for viruses in blood and stool samples from humans and animals, screen blood samples during outbreaks like the current pandemic, and study interactions between viruses and their hosts.

The virus that causes COVID-19 is so virulent that there are only a few cryo-EM labs in the world that can study it with a high enough level of biosafety controls, Jin said. So for this study, the research team looked at a much milder coronavirus strain called NL63, which causes common cold symptoms and is responsible for about 10% of human respiratory disease each year. It's thought to attach to the same receptors on the surfaces of human cells as the COVID-19 virus does.

Rather than chemically removing and purifying NL63's spike proteins, the researchers flash-froze whole, intact viruses into a glassy state that preserves the natural arrangement of their components. Then they made thousands of detailed images of randomly oriented viruses using cryo-EM instruments at the Stanford-SLAC Cryo-EM Facilities, ­­­­digitally extracted the bits that contained spike proteins, and combined them to get high-resolution pictures.

"The structure we saw had exactly the same structure as it does on the virus surface, free of chemical artifacts," Jin said. "This had not been done before."

The team also identified places where sugar molecules attach to the spike protein in a process called glycosylation, which plays an important role in the virus's life cycle and in its ability to evade the immune system. Their map included three glycosylation sites that had been predicted but never directly seen before.

Although a German group has used a similar method to digitally extract images of the spike protein from SARS-CoV-2, Jin said, they had to fix the virus in formaldehyde first so there would be no danger of it infecting anyone, and this treatment may cause chemical changes that interfere with seeing the true structure.

Going forward, she said, the team would like to find out how the part of the spike that binds to receptors on human cells is activated, and also use the same technique to study spike proteins from the virus that causes COVID-19, which would require specialized biohazard containment facilities.

Hospitalized COVID-19 patients have a greater risk of dying if they are men or if they are obese or have complications from diabetes or hypertension, according to a new study conducted by University of Maryland School of Medicine (UMSOM) researchers. In a study published in the journal Clinical Infectious Diseases, the researchers evaluated nearly 67,000 hospitalized COVID-19 patients in 613 hospitals across the country to determine the link between certain common patient characteristics and the risk of dying from COVID-19.

Their analysis found that men had a 30 percent higher risk of dying compared to women of the same age and health status. Hospitalized patients who were obese, had hypertension or poorly managed diabetes had a higher risk of dying compared to those who did not have these conditions. Those aged 20 to 39 with these conditions had the biggest difference in their risk of dying compared to their healthier peers.

"Predicting which hospitalized COVID-19 patients have the highest risk of dying has taken on urgent importance as cases and hospitalizations in the U.S. continue to surge to record high numbers during the month of December," said study corresponding author Anthony D. Harris, MD, MPH, Professor of Epidemiology and Public Health at UMSOM. "Knowledge is power in many ways, so I think understanding which hospitalized COVID-19 patients are at highest risk of mortality can help guide difficult treatment decisions."

For example, higher-risk patients may be given the drug remdesivir earlier in their hospitalization to help prevent severe complications or may be considered for closer monitoring or ICU admission. Healthcare providers may also want to consider these risks when determining which COVID-19 patients could benefit the most from the new monoclonal antibody therapies that, if given in the first few days of the infection, can reduce the risk of hospitalization.

Age remained the strongest predictor of mortality from COVID-19. Overall, nearly 19 percent of hospitalized COVID-19 patients died from their infection with the lowest mortality among pediatric patients, which was less than 2 percent. Mortality rates increased with each decade of life with the highest mortality, 34 percent, among those aged 80 and older.

"Older patients still have the highest risk of dying, but younger patients with obesity or hypertension have the highest risk of dying relative to other patients their age without these conditions," said study lead author Katherine E. Goodman, JD, PhD, a postdoctoral fellow in the Department of Epidemiology and Public Health at UMSOM. "Doctors may want to be paying extra attention to these younger patients when they're hospitalized to ensure they detect any complications quickly."

The researchers also found some good news in their study findings. Death rates among hospitalized patients have fallen dramatically since the early weeks of the pandemic in April. This is likely due to the availability of new treatments and more knowledge in the medical community on how to properly manage and care for hospitalized patients.

"As we head into what may be the darkest weeks of the pandemic, it is reassuring to know that our researchers are continuing to make important advances that could help guide the decision-making skills of healthcare workers in the field," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine. "I am incredibly proud of our faculty and what they have accomplished to help save the lives of COVID-19 patients as we eagerly await a vaccine."

While the SARS-CoV-2 virus has dominated the news this past year, researchers continue to study the health effects of the Zika virus, which has been reported in 86 countries globally.

The Zika virus is primarily transmitted by the bite of an infected mosquito from the Aedes genus. However, it can also be passed through sexual contact, blood transfusions, organ transplants, and between mother and baby during pregnancy. The virus has been documented to cause a range of birth defects, including microcephaly and various neurological, musculoskeletal, and eye abnormalities.

A new study from Glenn Yiu, associate professor in the Department of Ophthalmology, and Koen Van Rompay, a core scientist at the California National Primate Research Center, found that Zika infection during the first trimester of pregnancy can impact fetal retinal development and cause congenital ocular anomalies. The virus does not appear to affect ocular growth postnatally, however.

"It has been known that congenital infection with the Zika virus can lead to eye defects, but it was unclear if the virus continues to replicate or affect eye development after birth," Yiu said. "Our study in rhesus monkeys suggest that the virus primarily affects fetal development during pregnancy, but not the growth of eye after birth."

In this collaboration between the UC Davis Eye Center and the California National Primate Research Center, two pregnant rhesus monkeys were infected with Zika virus late in the first trimester. The ocular development of the Zika-exposed infants was then studied for two years following their birth.

Ocular birth defects

The Zika-exposed infant monkeys did not display microcephaly or apparent neurological or behavioral deficits. The infants did exhibit several ocular birth defects, however. The defects included large colobomas, a missing gap in the eye due to abnormal development. The Zika-exposed infant monkeys also exhibited a loss of photoreceptors -- the light-sensing cells of the retina -- and retinal ganglion neuron, which helps transmit visual information to the brain.

Despite congenital ocular malformations at birth, their eyes appeared to follow normal development during their first two years.

The findings suggest that ocular defects due to Zika infection primarily occur in utero and likely do not have a continued impact on ocular development after birth.

Rhesus macaques are natural hosts of the virus and share similar immune and ocular characteristics to humans, including blood-retinal barrier characteristics and the unique presence of a macula, making them superior animal models of the infection than typical laboratory animals like mice and rats. The findings were published in JCI Insight, an open-access peer-reviewed journal dedicated to biomedical research.

FAYETTEVILLE, Ark. - A University of Arkansas biologist is part of a global team of researchers developing a strategy to detect and intercept diseases emerging from wildlife in Africa that could eventually infect humans.

Assistant professor Kristian Forbes, along with colleagues from Africa, Europe and North America, have proposed a four-part approach to detect and contain zoonotic diseases, those that begin in animals but spillover into humans, like COVID-19 and HIV.

"A lot of research effort to prepare against the threat of novel disease emergences of wildlife viruses has been to identify unknown viruses in wildlife that might someday infect humans," Forbes said. "These efforts have been very successful for identifying new viruses; indeed, thousands have been discovered, but we don't currently have the tools to know which of them pose the most immediate risks to human health."

To enable fast detection of new zoonotic disease outbreaks, the team proposes a system of procuring and screening samples from hospital patients with fevers of unknown origin, analyzing samples from suspicious fatalities of unknown cause, testing blood serum in high-risk or sentinel groups and analyzing samples that have already been collected and archived. The team outlined their approach in a recent article published in the journal The Lancet Microbe.

None of these methods are new, Forbes said. But to date they have not been combined into a continent-wide program aimed at rapid detection.

"Given limitations to the current model for preventing disease emergences, our article focuses on a coordinated and widespread strategy for early detection so that novel disease outbreaks can be intercepted before they potentially become global pandemics."

Researchers from the National Graphene Institute at the University of Manchester and the University of Pennsylvania have identified ultra-fast gas flows through the tiniest holes in one-atom-thin membranes, in a study published in Science Advances.

The work - alongside another study from Penn on the creation of such nano-porous membranes - holds promise for numerous application areas, from water and gas purification to monitoring of air quality and energy harvesting.

In the early 20th century, renowned Danish physicist Martin Knudsen formulated theories to describe gas flows. Emerging new systems of narrower pores challenged the Knudsen descriptions of gas flows, but they remained valid and it was unknown at which point of diminishing scale they might fail.

The Manchester team - led by Professor Radha Boya, in collaboration with the University of Pennsylvania team, led by Professor Marija Drndi? - has shown for the first time that Knudsen's description seems to hold true at the ultimate atomic limit.

The science of two dimensional (2D)-materials is progressing rapidly and it is now routine for researchers to make one-atom-thin membranes. Professor Drndi?'s group in Pennsylvania developed a method to drill holes, one atom wide, on a monolayer of tungsten disulphide. One important question remained, though: to check if the atomic-scale holes were through and conducting, without actually seeing them manually, one by one. The only way previously to confirm if the holes were present and of the intended size, was to inspect them in a high resolution electron microscope.

Professor Boya's team developed a technique to measure gas flows through atomic holes, and in turn use the flow as a tool to quantify the hole density. She said: "Although it is beyond doubt that seeing is believing, the science has been pretty much limited by being able to only seeing the atomic pores in a fancy microscope. Here we have devices through which we can not only measure gas flows, but also use the flows as a guide to estimate how many atomic holes were there in the membrane to start with."

J Thiruraman, the co-first author of the study, said: "Being able to reach that atomic scale experimentally, and to have the imaging of that structure with precision so you can be more confident it's a pore of that size and shape, was a challenge."

Professor Drndi? added: "There's a lot of device physics between finding something in a lab and creating a usable membrane. That came with the advancement of the technology as well as our own methodology, and what is novel here is to integrate this into a device that you can actually take out, transport across the ocean if you wish [to Manchester], and measure."

Dr Ashok Keerthi, another lead author from the Manchester team, said: "Manual inspection of the formation of atomic holes over large areas on a membrane is painstaking and probably impractical. Here we use a simple principle, the amount of the gas the membrane lets through is a measure of how holey it is."

The gas flows achieved are several orders of magnitude larger than previously observed flows in angstrom-scale pores in literature. A one-to-one correlation of atomic aperture densities by transmission electron microscopy imaging (measured locally) and from gas flows (measured on a large scale) was combined by this study and published by the team. S Dar, a co-author from Manchester added: "Surprisingly there is no/minimal energy barrier to the flow through such tiny holes."

Professor Boya added: "We now have a robust method for confirming the formation of atomic apertures over large areas using gas flows, which is an essential step for pursuing their prospective applications in various domains including molecular separation, sensing and monitoring of gases at ultra-low concentrations."

AMHERST, Mass. - In a new study of tidal marsh resilience to sea level rise, geologist and first author Brian Yellen at the University of Massachusetts Amherst and colleagues observed that Hudson River Estuary marshes are growing upward at a rate two to three times faster than sea level rise, "suggesting that they should be resilient to accelerated sea level rise in the future," he says.

Writing in Earth Surface Processes and Landforms, Yellen and colleagues documented that more than half of Hudson River tidal marshes formed since 1850. That year, the channel was straightened and a riverside railroad, berms, jetties and human-made islands of dredged soil were built. This all trapped sediment and created backwaters that often - but not always - turned into marshes, an "unintended result of early industrial development," they state.

"In one case, historical aerial photos document this transition occurring in less than 18 years, offering a timeframe for marsh development," they point out. Yellen's co-authors are colleagues Jonathan Woodruff, Caroline Ladlow and undergraduate Waverly Lau at UMass Amherst, plus Sarah Fernald at New York's department of environmental conservation and David K. Ralston of Woods Hole Oceanographic Institution.

Yellen notes that for this "very collaborative" study, the researchers took advantage of "an experiment that has already happened over decades or centuries. Many of these accidental tidal marshes worked; they protect the shoreline and provide one of the richest ecosystems in terms of direct ecological and human benefits."

Further, marshes are "really useful," he adds - as a first line of defense against coastal flooding, essential habitat for juvenile commercial fish species, they store huge amounts of carbon that mitigates climate change, they provide habitat for migratory birds, filter nutrients coming off the land "and they're beautiful."

Yellen and colleagues write that these tidal wetlands "currently trap roughly 6% of the Hudson River's sediment load. Results indicate that when sediment is readily available, freshwater tidal wetlands can develop relatively rapidly in sheltered settings. The study sites serve as useful examples to help guide future tidal marsh creation and restoration efforts."

Their research involved seven sites spanning more than 100 miles of the Hudson Estuary, "from Wall Street up to Albany," Yellen says. The bays where tidal marshes developed started out six to seven feet deep and have steadily grown vertically. "One concern for marshes globally is that they will be drowned by rising sea level, but this case study shows how marshes can be created and it gave us some timing benchmarks for what is considered a tricky ecosystem restoration," he adds.

The researchers used two main methods to investigate the river's history and resilience in the face of sea level rise - sediment cores that shed light on how fast sediment accumulated and historical maps, charts and aerial photos to determine how the sites have changed over time.
Yellen summarizes, "As long as there is space for sediment to accumulate, new marshes can develop. There is a community of land trusts up and down the river who are planning now for future sea level rise and considering where new marshes can form. This research will help them and state agencies guide land acquisition and land conservation strategies adjacent to the river to 2100 and beyond."

The research, part of the Dams and Sediment in the Hudson (DaSH) project, was supported by a grant to Ralston from NOAA's National Estuarine Research Reserve Collaborative, plus the U.S. Geological Survey and the Department of Interior Northeast Climate Adaptation Science Center at UMass Amherst.

Also, Lau received a Polgar Fellowship from the Hudson River Foundation for her senior thesis project. She took the lead on one of the sites and made a short film about tidal marshes around the world and the Hudson River marsh near her home in Queens.

URBANA, Ill. ¬- When agrochemical and pharmaceutical companies develop new products, they must test extensively for potential toxicity before obtaining regulatory approval. This testing usually involves lengthy and expensive animal studies.

A research team at University of Illinois has developed a gene biomarker identification technique that cuts the testing process down to a few days while maintaining a high level of accuracy.

"The aim of this research was to identify the smallest set of indicators from the liver to predict toxicity and potential liver cancer," says Zeynep Madak-Erdogan, associate professor in the Department of Food Science and Human Nutrition at U of I and a lead author on the study.

"The agrochemical industry has a pipeline where they test new compounds in terms of toxicity-related endpoints. Liver toxicity is one of the most important endpoints, because the liver is the organ that receives the blood supply and cleans it, making it one of the biggest targets in terms of environmental toxic action," Madak-Erdogan explains.

Normally, companies do this through long-term animal experiments, she adds. They track animals for up to a year to see if they develop liver cancer after exposure to these compounds. The studies require thousands of mice or rats, and a lot of human time taking care of the animals, collecting samples, and analyzing the data.

The study, published in Scientific Reports, identifies a biomarker gene signature that indicates potential liver toxicity just 24 hours after exposure.

Madak-Erdogan and her colleagues analyzed information from a large database maintained by the National Institute of Environmental Health Sciences. In collaboration with scientists at the U of I National Center for Supercomputing Applications (NCSA), they used machine learning approaches to identify gene biomarkers in messenger RNA to predict future toxicity.

"From designing new molecules to identifying novel biological targets, machine learning approaches are playing a key role in accelerating drug target identification and validation," explains Colleen Bushell, director of NCSA's Healthcare Innovation Program Office and co-author on the study.

While this study is not the first to employ such techniques, it is the most comprehensive, Madak-Erdogan says. The researchers used a large amount of data and multiple machine learning techniques in order to identify the methods that provide the fastest and most accurate results.

"We are assessing the best prediction techniques and finding the best indicators for liver toxicity. Instead of going for months or years, now we can just treat a few mice for 24 hours, collect livers, look at the biomarkers we identified, and predict whether the animal will potentially develop liver cancer or not," she explains.

The study's results can be used broadly by toxicologists and other scientists, and can help the agrochemical and pharmaceutical industry improve their testing capabilities.

"Our findings show machine learning approaches are definitely very valuable in analyzing the vast amount of biological data that we create in our research activities. Collaboration between life sciences and computer sciences is very important for this work," Madak-Erdogan concludes.

Bacteria often show very strong biogeography - some bacteria are abundant in specific locations while absent from others - leading to major questions when applying microbiology to therapeutics or probiotics: how did the bacteria get into the wrong place? How do we add the right bacteria into the right place when the biogeography has gotten 'out of whack'?

These questions, though, have one big obstacle, bacteria are so tiny and numerous with very diverse and complicated populations which creates major challenges to understanding which subgroups of bacteria live where and what genes or metabolic abilities allow them to thrive in these 'wrong' places.

In a new study published in Genome Biology researchers led by Harvard University examined the human oral microbiome and discovered impressive variability in bacterial subpopulations living in certain areas of the mouth.

"As microbial ecologists, we are fascinated by how bacteria can seemingly divide up any habitat into various niches, but as humans ourselves, we also have this innate curiosity about how microbes pattern themselves within our bodies," said lead author Daniel R. Utter, PhD candidate in the Department of Organismic and Evolutionary Biology, Harvard University.

Recent developments in sequencing and bioinformatic approaches have offered new ways to untangle the complexity of bacterial communities. Utter and Colleen Cavanaugh, Edward C. Jeffrey Professor of Biology in the Department of Organismic and Evolutionary Biology, Harvard University, teamed up with researchers at the Marine Biological Laboratory, Woods Hole, University of Chicago, and The Forsyth Institute to apply these state-of-the-art sequencing and analysis approaches to get a better picture of the oral microbiome.

"The mouth is the perfect place to study microbial communities," according to co-author A. Murat Eren, assistant professor in the Department of Medicine at the University of Chicago. "Not only is it the beginning of the GI tract, but it's also a very special and small environment that's microbially diverse enough that we can really start to answer interesting questions about microbiomes and their evolution."

The mouth contains a surprising amount of site-specific microbes in different areas. For instance, the microbes found on the tongue are very different from the microbes found on the plaque on teeth. "Your tongue microbes are more similar to those living on someone else's tongue than they are to those living in your throat or on your gums!" said Eren.

The team scoured public databases and downloaded 100 genomes that represented four species of bacteria commonly found in the mouth, Haemophilus parainfluenzae and the three oral species of the genus Rothia, and used them as references to investigate their relatives sampled in hundreds of volunteers' mouths from the Human Microbiome Project (HMP).

"We used these genomes as a starting point, but quickly moved beyond them to probe the total genetic variation among the trillions of bacterial cells living in our mouths," said Utter. "Because, at the end of the day, that's what we're curious about, not the arbitrary few that have been sequenced."

Using this recently-developed approach called metapangenomics, which combines pangenomes (the sum of all genes found in a set of related bacteria) with metagenomics (the study of the total DNA coming from all bacteria in a community), allowed the researchers to conduct an in-depth examination of the genomes of the microbes which led to a shocking discovery.

"We found a tremendous amount of variability," said Utter. "But we were shocked by the patterning of that variability across the different parts of the mouth; specifically, between the tongue, cheek, and tooth surfaces."

For example, within a single microbe species the researchers found distinct genetic forms that were strongly associated to a single, different site within the mouth. In many cases, the team was able to identify a handful of genes that might explain a particular bacterial group's specific habitat. Applying metapangenomics the researchers were also able to identify specific ways free-living bacteria in people's mouths differed from their lab-grown relatives.

"The resolution afforded by these techniques -- via the direct comparison of genomes of "domesticated" and "wild" bacteria -- allows us to dissect these differences gene by gene," notes Cavanaugh. "We were also able to identify novel bacterial strains related to, but different than, those we have in culture."

"Having identified some really strong bacterial candidates that could determine adaptation to a particular habitat, we would like to experimentally test these hypotheses," said Cavanaugh. These findings could potentially be the key to unlocking targeted probiotics, where scientists could use what's been learned about each microbe's habitat's requirements to engineer beneficial microbes to land in a specified habitat.

"The mouth is so easily accessible that people have been working on bacteria from the mouth for a long time," said co-author Jessica Mark Welch, associate scientist at the Marine Biological Laboratory.

"Every environment we look at has these really complicated, complex communities of bacteria, but why is that?" said Mark Welch. "Understanding why these communities are so complex and how the different bacteria interact will help us better understand how to fix a bacterial community that's damaging our health, telling us which microbes need to be removed or added back in."

This study and others like it can provide new insights on the role of oral microbes in human health. "The ability to identify specific genes behind habitat adaptation has been somewhat of a 'holy grail' in microbial ecology," said Utter. "We are very excited for our contributions in this area!"

Wearing a face covering in public is dependent upon how often people observe others wearing them, according to recent findings. Other important motivating factors are among findings of a national study undertaken by the U.S. Centers for Disease Control and Prevention through lead author Jack Barile, interim director of the Social Science Research Institute in University of Hawai'i at Mānoa's College of Social Sciences. More than 1,000 U.S. adults, ages 18 and older, who are representative of the U.S. population by gender, age, region, race/ethnicity and education, were surveyed.

"In this study, we examined what motivators are behind an individual's choice to wear or not wear a face covering in public," Barile said. "This understanding is critical to developing successful messaging strategies to encourage acceptance and use of face coverings to prevent the transmission of SARS-CoV-2, the virus that causes COVID-19."

The study suggests that being female, perceived importance of others wanting the respondent to wear a face covering, confidence to wear a face covering and perceived importance of personal face covering use were all factors positively associated with intention to wear a face covering in public.

No evidence was found that a perceived susceptibility to becoming ill and a perceived severity of COVID-19 correlated with an increase in the intent to use a face covering in public.

"The survey allowed us to explore both the barriers and facilitators to the public's use of face coverings, as well as to identify possible pathways through which the use of face coverings while in public could be increased among the U.S. population," Barile said. "Based on our findings, it is possible that messaging strategies that focus on susceptibility to and severity of COVID-19 may not be as effective as targeting actions that influence individual intentions and social norms."

Barile noted that, while distributions of the first vaccine to prevent COVID-19 have begun in the U.S., health officials predict that it will be months before the vaccine is readily available to all individuals who seek it.

"This makes mask wearing in public, especially when social distancing is difficult to maintain, an essential component in the continuing effort to reduce the virus' transmission," he said.

The study was published in the Annals of Behavioral Medicine, the Society of Behavioral Medicine's flagship journal. It publishes original empirical articles on behavioral medicine and the integration of biological, psychosocial and behavioral factors and principles.

In the aftermath of megafires that devastated forests of the western United States, attention turns to whether forests will regenerate on their own or not. Forest managers can now look to a newly enhanced, predictive mapping tool to learn where forests are likely to regenerate on their own and where replanting efforts may be beneficial.

The tool is described in a study published in the journal Ecological Applications by researchers from the University of California, Davis; U.S. Geological Survey (USGS), Cal Fire and the U.S. Forest Service.

"Huge fires are converting forested areas to landscapes devoid of living trees," said lead author Joseph Stewart, a postdoctoral researcher at UC Davis and with USGS. "Managers need timely and accurate information on where reforestation efforts are needed most."

The tool, also known as the Post-fire Spatial Conifer Regeneration Prediction Tool (POSCRPT), helps forest managers identify within weeks after a fire where sufficient natural tree regeneration is likely and where artificial planting of seedlings may be necessary to restore the most vulnerable areas of the forest.

NOT SO EVERGREEN

Conifers, or plants with cones such as pine trees, dominate many forests in western North America. The study found that conifers are less likely to regenerate after fires when seedlings face drier climate conditions, especially in low-elevation forests that already experience frequent drought stress. Overall, fewer conifers are expected to grow in California's lower elevations following wildfire due to climate and drought conditions.

"We found that when forest fires are followed by drought, tree seedlings have a harder time, and the forest is less likely to come back," said Stewart.

A UC Davis team collected post-fire recovery data from more than 1,200 study plots in 19 wildfires that burned between 2004 and 2012, as well as 18 years of forest seed production data. Ecologists at USGS collected and identified over 170,000 seeds from hundreds of seed traps. The scientists combined these data with multispectral satellite imagery, forest structure maps, climate and other environmental data to create spatial models of seed availability and regeneration probability for different groups of conifers, including pines and firs.

Forest managers have used a prototype of the tool in recent years to better understand where to focus regeneration efforts. The new upgrade incorporates information on post-fire climate and seed production and includes an easy-to-use web interface expected to increase the tool's accuracy and use.

"This work is a great example of how multiple partners can come together to solve major resource management problems that are arising from California's climate and fire trends," said co-author Hugh Safford, regional ecologist for the USDA Forest Service's Pacific Southwest Region and a member of the research faculty at UC Davis.

A UCLA-led study may help explain how COVID-19 increases the risk for stroke. Scientists made the finding by running fluid spiked with a COVID-19-like protein through a 3D-printed model of the arteries of a patient who had suffered a stroke.

Although COVID-19 was first identified by its severe respiratory symptoms, the virus has caused strokes in young people who had no known risk factors. But little is known about how the virus increases the risk for stroke.

To learn more, UCLA researchers used a 3D-printed silicone model of blood vessels in the brain to mimic the forces generated by blood pushing through an artery that is abnormally narrowed, a condition called intracranial atherosclerosis. They showed that as those forces act on the cells lining the artery, and increase the production of a molecule called angiotensin-converting enzyme 2, or ACE2, which the coronavirus uses to enter cells on the surface of blood vessels.

"The flow directly influences ACE2 expression," said Dr. Jason Hinman, an assistant professor of neurology at the David Geffen School of Medicine at UCLA and the study's senior author.

In addition to Hinman, the study's authors are neurologists at the Geffen School of Medicine and scientists from UC San Francisco and the Veterans Health Administration. The paper was published (PDF) in Stroke.

UCLA researchers created the model using data from CT scans of blood vessels in a human brain. They then lined the inner surfaces of the models with endothelial cells, the type of cells that line human blood vessels. The models enabled the researchers to mimic the same forces that would act on real blood vessels during a COVID-19 infection.

To confirm whether coronavirus bobbing along in the bloodstream could latch onto the ACE2 on the endothelial cells in the brain, researchers produced imitation "viruses" -- fatty molecules studded with the spike proteins that coronavirus uses to bind to ACE2. Previous research indicated that the coronavirus binds to endothelial cells in other organs, but it was unknown whether that was also happening in the brain.

After creating the new model, researchers confirmed the particles did indeed interact with the cells lining the blood vessel, mostly in the regions of the brain with higher levels of ACE2.

"This finding could explain the increased incidence of strokes seen in COVID-19 infections," Hinman said.

Another discovery offered an insight that eventually could help identify people with COVID-19 who may have a higher risk for stroke. When the scientists analyzed which genes were turned on in the endothelial cells after the coronavirus spike proteins bound to them, they found that the genes that were activated were a specific set of immune-response genes that are found in brain blood vessel cells, but not in endothelial cells from other organs of the body.

"There's a unique brain endothelial response to the virus that may be helpful in identifying patients who are have a higher risk for stroke," Hinman said.

The researchers intend to conduct follow-up studies using a live coronavirus in the 3D-printed blood vessel model, which would further confirm the results of the current study and clarify which COVID-19 patients may have a higher risk for stroke.

Plants have the same variation in body clocks as that found in humans, according to new research that explores the genes governing circadian rhythms in plants.

The research shows a single letter change in their DNA code can potentially decide whether a plant is a lark or a night owl. The findings may help farmers and crop breeders to select plants with clocks that are best suited to their location, helping to boost yield and even the ability to withstand climate change.

The circadian clock is the molecular metronome which guides organisms through day and night - cockadoodledooing the arrival of morning and drawing the curtains closed at night. In plants, it regulates a wide range of processes, from priming photosynthesis at dawn through to regulating flowering time.

These rhythmic patterns can vary depending on geography, latitude, climate and seasons - with plant clocks having to adapt to cope best with the local conditions.

Researchers at the Earlham Institute and John Innes Centre in Norwich wanted to better understand how much circadian variation exists naturally, with the ultimate goal of breeding crops that are more resilient to local changes in the environment - a pressing threat with climate change.

To investigate the genetic basis of these local differences, the team examined varying circadian rhythms in Swedish Arabidopsis plants to identify and validate genes linked to the changing tick of the clock.

Dr Hannah Rees, a postdoctoral researcher at the Earlham Institute and author of the paper, said: "A plant's overall health is heavily influenced by how closely its circadian clock is synchronised to the length of each day and the passing of seasons. An accurate body clock can give it an edge over competitors, predators and pathogens.

"We were interested to see how plant circadian clocks would be affected in Sweden; a country that experiences extreme variations in daylight hours and climate. Understanding the genetics behind body clock variation and adaptation could help us breed more climate-resilient crops in other regions."

The team studied the genes in 191 different varieties of Arabidopsis obtained from across the whole of Sweden. They were looking for tiny differences in genes between these plants which might explain the differences in circadian function.

Their analysis revealed that a single DNA base-pair change in a specific gene - COR28 - was more likely to be found in plants that flowered late and had a longer period length. COR28 is a known coordinator of flowering time, freezing tolerance and the circadian clock; all of which may influence local adaptation in Sweden.

"It's amazing that just one base-pair change within the sequence of a single gene can influence how quickly the clock ticks," explained Dr Rees.

The scientists also used a pioneering delayed fluorescence imaging method to screen plants with differently-tuned circadian clocks. They showed there was over 10 hours difference between the clocks of the earliest risers and latest phased plants - akin to the plants working opposite shift patterns. Both geography and the genetic ancestry of the plant appeared to have an influence.

"Arabidopsis thaliana is a model plant system," said Dr Rees. "It was the first plant to have its genome sequenced and it's been extensively studied in circadian biology, but this is the first time anyone has performed this type of association study to find the genes responsible for different clock types.

"Our findings highlight some interesting genes that might present targets for crop breeders, and provide a platform for future research. Our delayed fluorescence imaging system can be used on any green photosynthetic material, making it applicable to a wide range of plants. The next step will be to apply these findings to key agricultural crops, including brassicas and wheat."

The results of the study have been published in the journal Plant, Cell and Environment.

Scientists in Japan's brain science project have used machine intelligence to improve the accuracy and reliability of a powerful brain-mapping technique, a new study reports.

Their development, published on December 18th in Scientific Reports, gives researchers more confidence in using the technique to untangle the human brain's wiring and to better understand the changes in this wiring that accompany neurological or mental disorders such as Parkinson's or Alzheimer's disease.

"Working out how all the different brain regions are connected - what we call the connectome of the brain - is vital to fully understand the brain and all the complex processes it carries out," said Professor Kenji Doya, who leads the Neural Computation Unit at the Okinawa Institute of Science and Technology Graduate University (OIST).

To identify connectomes, researchers track nerve cell fibers that extend throughout the brain. In animal experiments, scientists can inject a fluorescent tracer into multiple points in the brain and image where the nerve fibers originating from these points extend to. But this process requires analyzing hundreds of brain slices from many animals. And because it is so invasive, it cannot be used in humans, explained Prof. Doya.

However, advances in magnetic resonance imaging (MRI) have made it possible to estimate connectomes non-invasively. This technique, called diffusion MRI-based fiber tracking, uses powerful magnetic fields to track signals from water molecules as they move - or diffuse - along nerve fibers. A computer algorithm then uses these water signals to estimate the path of the nerve fibers throughout the whole brain.

But at present, the algorithms do not produce convincing results. Just like how photographs can look different depending on the camera settings chosen by a photographer, the settings - or parameters - chosen by scientists for these algorithms can generate very different connectomes.

"There are genuine concerns with the reliability of this method," said Dr. Carlos Gutierrez, first author and postdoctoral researcher in the OIST Neural Computation Unit. "The connectomes can be dominated by false positives, meaning they show neural connections that aren't really there."

Furthermore, the algorithms struggle to detect nerve fibers that stretch between remote regions of the brain. Yet these long-distance connections are some of the most important for understanding how the brain functions, Dr. Gutierrez said.

In 2013, scientists launched a Japanese government-led project called Brain/MINDS (Brain Mapping by Integrated Neurotechnologies for Disease Studies) to map the brains of marmosets -- small nonhuman primates whose brains have a similar structure to human brains.

The brain/MINDS project aims to create a complete connectome of the marmoset brain by using both the non-invasive MRI imaging technique and the invasive fluorescent tracer technique.

"The data set from this project was a really unique opportunity for us to compare the results from the same brain generated by the two techniques and determine what parameters need to be set to generate the most accurate MRI-based connectome," said Dr. Gutierrez.

In the current study, the researchers set out to fine-tune the parameters of two different widely-used algorithms so that they would reliably detect long-range fibers. They also wanted to make sure the algorithms identified as many fibers as possible while minimally pinpointing ones that were not actually present.

Instead of trying out all the different parameter combinations manually, the researchers turned to machine intelligence.

To determine the best parameters, the researchers used an evolutionary algorithm. The fiber tracking algorithm estimated the connectome from the diffusion MRI data using parameters that changed - or mutated - in each successive generation. Those parameters competed against each other and the best parameters - the ones that generated connectomes that most closely matched the neural network detected by the fluorescent tracer - advanced to the next generation.

The researchers tested the algorithms using fluorescent tracer and MRI data from ten different marmoset brains.

But choosing the best parameters wasn't simple, even for machines, the researchers found. "Some parameters might reduce the false positive rate but make it harder to detect long-range connections. There's conflict between the different issues we want to solve. So deciding what parameters to select each time always involves a trade-off," said Dr. Gutierrez.

Throughout the multiple generations of this "survival-of-the-fittest" process, the algorithms running for each brain exchanged their best parameters with each other, allowing the algorithms to settle on a more similar set of parameters. At the end of the process, the researchers took the best parameters and averaged them to create one shared set.

"Combining parameters was an important step. Individual brains vary, so there will always be a unique combination of parameters that works best for one specific brain. But our aim was to come up with the best generic set of parameters that would work well for all marmoset brains," explained Dr. Gutierrez.

The team found that the algorithm with the generic set of optimized parameters also generated a more accurate connectome in new marmoset brains that weren't part of the original training set, compared to the default parameters used previously.

The striking difference between the images constructed by algorithms using the default and optimized parameters sends out a stark warning about MRI-based connectome research, the researchers said.

"It calls into question any research using algorithms that have not been optimized or validated," cautioned Dr. Gutierrez.

In the future, the scientists hope to make the process of using machine intelligence to identify the best parameters faster, and to use the improved algorithm to more accurately determine the connectome of brains with neurological or mental disorders.

"Ultimately, diffusion MRI-based fiber tracking could be used to map the whole human brain and pinpoint the differences between healthy and diseased brains," said Dr. Gutierrez. "This could bring us one step closer to learning how to treat these disorders."

Sea level could rise higher than current estimates by 2100 if climate change is unchallenged, according to a new assessment.

Its authors say understanding the way strong global heating affects polar ice sheets will be crucial to projecting sea level rise over the next century. However, uncertainties remain and current knowledge about ice sheets suggests sea-level rise under continued strong warming could be higher than the Intergovernmental Panel on Climate Change (IPCC) 'likely' range by 2100.

The authors of the study, published today in the journal One Earth, also suggest ways scientists can make predictions more certain, by improving our understanding of ice-sheet dynamics, such as how they interact with warming oceans and how they fracture and break apart.

Lead author Professor Martin Siegert, from the Grantham Institute - Climate Change and Environment at Imperial College London, said: "Greenhouse gas emissions are still on the rise, and strong heating, of more than 4°C by 2100, is well within the realm of the possible if emissions continue unabated.

"Currently, hundreds of millions of people live in regions susceptible to coastal flooding, and the likelihood of even worse flooding will significantly increase with severe sea-level rise. The sea-level rise we have already faced has been somewhat mitigated by flood barriers and other measures, but we are unprepared for higher rates of rise that could overwhelm these measures. If we don't do more to avert dangerous global heating, we may reach a point where we can no longer protect people."

The team reviewed current models of the effect of warming on ice sheets that the IPCC's 2019 report on sea-level rise relies on. For the strong heating scenario of more than 4°C of temperature rise by 2100, the report gave a 'likely' range for sea-level rise of between 0.61 and 1.10 metres above 1950 levels.

However, the team's analysis showed that ice sheet models do not include sufficient detail on key processes that may lead to significant mass loss under strong warming, meaning sea level rise above the IPCC's likely range is far more possible than below it.

Co-author John Englander, President and Founder of the Rising Seas Institute, said: "Sea-level rise will be one of the most challenging issues faced by society in the coming decades. We need to recognize that we cannot stand by and wait for clarity about actual sea-level rise to begin planning for it.

"Waiting for better confidence in predictions is not a reason to delay building a margin of safety, for example into building codes and zoning, recognising the inevitability of sea-level rise and its catastrophic implications."

There are two main ways sea level can rise substantially at a global level. Throughout the twentieth century, rise has been dominated by thermal expansion - added heat driving water molecules apart, expanding the volume of the ocean water. In the twenty-first century, however, the second mechanism has become dominant: the addition of water from melting ice sheets and glaciers.

While sea-level rise due to thermal expansion can be predicted using relatively simple relationships between the temperature and the expansion, ice sheets and glaciers respond to rising temperatures in complex and interconnected ways that make prediction more fraught.

Researchers looking ahead to the next century of climate change and its increasing impact on human society, nature and the environment often look back at previous episodes of natural climate change for clues as to how various earth systems will react.

At the end of the last ice age, there is evidence that ice sheets responded to warming by rapidly losing mass at rates that at times were higher than currently observed, leading to several metres of sea-level rise per century.

The team say this means current projections of sea-level rise may be underestimates, as the ice sheets may lose mass faster over the coming century than our current models predict.

To improve models and predictions, the authors identify key areas of research that are needed to fill in our gaps in knowledge. These include better mapping of the ground beneath glaciers and ice sheets, collection of data at the margin where glaciers meet the ocean, and improved coupling of models of the atmosphere, oceans, and ice sheets.

While the network of existing observations of ice sheet dynamics already gives scientists a very strong warning signal and causes for concern, the authors say these improvements could lead to a next-generation 'early warning system' focused on signals of rapid change in sea level, such as increases in ocean water temperature along the margins of ice sheets.

Professor Siegert said: "We already have a good start on an early warning system for dangerous sea-level rise, with satellites, airborne platforms, robotic devices, field investigators, and expert knowledge. While this network is growing and getting stronger, it has major weaknesses at ice-sheet boundaries that require urgent action. We need to develop an array of robotic devices in key parts of Antarctica and Greenland that are most vulnerable and capable of rapid sea-level rise in the future."

In the last decade, Neuroscientists have made major advances in their quest to study the brain. They can assemble complete wiring diagrams and catalogue the brain's many cell types. They've developed electrode arrays for recording electrical activity in individual neurons and placed itty bitty microscopes on the heads of mice to visualize their brain activity. However, almost shockingly, there are no tools to precisely measure the brain's principal output -- behavior - in freely moving animals.

Animal behavior is important to a broad range of disciplines, from neuroscience and psychology to ecology and pharmacology. Carefully studying a lab animal's behavior allows researchers to model human disease and gauge the effectiveness of new drugs. Psychologists observe it to understand how animals learn and respond to reward and punishment, while neuroscientists study it to understand how the brain produces movements. The difficulty in capturing the intricate details of an animal's natural behavior has forced scientists to study very simple and often unnatural tasks, leaving open the question of whether the insights gained can really lead to a general understanding of brain function.

But help may be on the way! In a paper published December 18 in Neuron researchers from Harvard University describe a newly developed behavioral monitoring system, CAPTURE (continuous appendicular and postural tracking using retroreflector embedding), that combines motion capture and deep learning to continuously track the three-dimensional movements of freely behaving animals. In the study, lead author Jesse Marshall, postdoctoral fellow in the Department of Organismic and Evolutionary Biology, Harvard University, and senior author Bence Ölveczky, Professor in the Department of Organismic and Evolutionary Biology, Harvard University, attached markers to rats' head, trunk, and limbs and used CAPTURE to record their natural behavior continuously for weeks.

Marshall's fascination with the concept of CAPTURE began as a graduate student working on a mouse model of Parkinson's. "We had developed really elaborate approaches to study how the brain is disrupted in parkinsonian mice, but our ability to measure their behavioral deficits was a far cry from the nuanced ways we can assess the impact of Parkinson's on human behavior," said Marshall. "It became clear to me that a major reason why so many drugs tested in mice don't translate to humans is that our ability to measure their effects on behavior is quite limited."

Marshall grew weary of the difficulties and constraints in relating brain activity to the animal's behavior and the field's emphasis on the 'brain-first' approach. But when he joined Ölveczky's lab he was met with interest and support. Ölveczky too recognized the primary importance of behavior and was eager to develop new tools to measure it.

"Our lab studies how skilled movements are learned and generated by the brain," said Ölveczky. "Traditionally, these studies are done by designing specific tasks and relating brain activity to simple behavioral readouts i.e. did the animal push this lever? Did the animal lick this port? Such observations tell us whether our rats solve the task, but says nothing about how they do it and that's exactly what we are interested in; how the brain learns and controls skilled movements. Getting at this required more precise and sophisticated readouts of behavior."

Marshall researched various technologies and settled on motion capture, the gold standard for measuring movements in humans and a technology perfected by Hollywood animators. He spent the first six months figuring out how to attach markers to his animals. He tried tattoos, adhesives, and hair dyes -- all without luck -- before settling on a somewhat unorthodox approach: body-piercings. Working with local veterinarians, the team engineered custom markers made of specialized reflective glass that are attached to the animals like tiny earrings. Marshall affixed these markers to 20 locations on the animal's head, trunk and limbs so he could reconstruct the three-dimensional position and configuration of the animal's major joints, so also the movements of its body.

"In contrast to traditional motion capture in humans, which is done in short bursts, we collected data continuously, 24/7," said Marshall. "This allowed us to really quantify everything rats do in their normal lives -- an atlas for behavior."

The team then looked at how behaviors change in disease and in response to drugs. For drugs, they administered caffeine and amphetamines to the animals. While both stimulants caused the rats to move around more, they did so in different ways. After caffeine, the animals ran and explored their cage as normal animals do when highly aroused. However, when on amphetamine their behavior shifted in strange new ways; the animals ran around in repeated sequential patterns.

For disease, the team studied a rat model of Fragile X syndrome, a form of autism, and was able to identify atypical patterns of grooming that hadn't been previously described. Scientists have long suspected that disrupted grooming could be used to model the motor stereotypies (repetitive movements or sounds) observed in autism, but before CAPTURE alterations in grooming patterns have been challenging to measure and reproduce. "For disease models, you really need to evaluate how the disease affects behavior and whether a particular compound or drug can reverse the specific deficits" said Ölveczky. "These effects can be very subtle and the more precise your behavioral measurements are, the better handle you'll have on the disease. This is one of the uses for this technology."

The team continues their studies by combining CAPTURE with neural recordings to describe the relationship between brain activity and behavior across the full set of natural behaviors an animal performs. They are also working with Google DeepMind to use CAPTURE to model animal behavior using deep neural networks. These studies will help model how the brain produces behavior and potentially make new advances in artificial intelligence possible.

"These technological developments mean that we can now finally open the door to understanding the organization of natural behavior and its biomechanical and neurobiological foundations," said Ölveczky.