Culture

Acute liver failure is a devastating, rapidly progressing disease that results in death in 80% of cases, unless an emergency liver transplant is performed. In the developed world, its leading cause is a substantial overdose of acetaminophen, also known as paracetamol.

In a study published in Nature Medicine, researchers from the labs of Profs. Eran Elinav and Ido Amit in the Immunology Department of the Weizmann Institute of Science have, in using mouse models of acute liver failure, discovered three new subsets of liver cells that orchestrate the development of this condition. The scientists also uncovered signals - from the gut microbiome as well as the diseased liver - that jointly activate these cells, and showed that selectively blocking these signals and depleting the microbiome led to marked improvement in liver function and prolonged survival in mice. An analysis of liver tissue from human patients with acute liver failure revealed a molecular pattern strikingly similar to the one identified in mice in the study, raising hopes that the findings in mice may in the future be translated into a treatment for humans.

Dr. Aleksandra Kolodziejczyk, a postdoctoral fellow in Elinav's lab, led this project in collaboration with other scientists at the Weizmann Institute of Science and Dr. Amir Shlomai of the Liver Institute, Rabin Medical Center.

Kolodziejczyk and her colleagues began their exploration by creating gene expression profiles of 45,000 individual mouse liver cells, ultimately generating a comprehensive liver cell atlas in conditions of health and acute liver failure. The scientists identified 49 cell subsets, of which three new subsets - among stellate, endothelial and Kupffer cells - became abnormally activated as the acute liver failure progressed in the mice. These previously undescribed cell subsets secreted a large variety of substances that attracted immune cells from outside the liver, which then contributed to its damage. All three new cell subtypes shared a characteristic expression pattern of 77 genes - a pattern controlled by the same regulatory protein, the transcription factor MYC - which suggested that these cells may be activated through a common program.

The researchers suspected the newly uncovered activation pathway could be regulated by signals from the gut microbiome. This makes anatomical sense, as the gastrointestinal tract drains into the liver though a large network of veins, directly exposing the liver to substances produced in the gut and by its microbes. When the scientists depleted the microbiome of the mice by administering wide-spectrum antibiotics, symptoms of liver failure were alleviated. Moreover, when they induced acute liver failure in germ-free mice, which lack a microbiome, the condition was much less severe than in regular mice. Further studies of mice with and without a gut microbiome revealed that during acute liver failure, distinct molecules generated by the microbiome accumulate in the liver, where they activate the MYC protein in the three liver cell subtypes that contribute to liver damage. In the absence of a microbiome, MYC activation was attenuated, leading to reduced liver damage.

Kolodziejczyk then worked out the molecular details of MYC activation. She found that the molecules coming from the microbiome activate the MYC program through surface receptors on the three cell subtypes that she had identified earlier as aggravating the liver failure. She also found that the MYC program was activated in the same manner - that is, through the same receptors on the three cell subtypes - by signals coming from liver cells damaged by paracetamol.

When the mice were genetically depleted of functioning receptors, given drugs that blocked MYC or otherwise had the signals between these receptors and MYC interrupted, they no longer developed acute liver failure and their survival was extended. Gene expression analysis of individual cells showed that in the treated mice, the three newly identified cell subtypes were no longer abnormally activated, and this reduced both the immune cell infiltration and the resultant liver damage.

Finally, the researchers teamed up with Dr. Shlomai to analyze liver samples from patients with acute liver failure and to compare them with samples from healthy liver donors. Those from the patients - but not from healthy donors - were characterized by robust MYC activation that was similar to the one observed in mice. These results raise the possibility that blocking the MYC program by drugs, coupled with microbiome modulation, may prove to be a potential treatment for acute liver failure.

"Our findings provide a first step towards achieving a comprehensive understanding of how the microbiome interacts with the host in contributing to acute liver failure," Elinav says. "Such knowledge could lead to a new treatment option for this cureless and devastating disorder."

Living organisms aren't the only things that evolve over time. Cultural practices change, too, and in recent years social scientists have taken a keen interest in understanding this cultural evolution. Much research has focused on psychological factors among individuals, like how our visual system constrains the shape of written characters.

But environmental factors like availability of materials or physical space likely play a role, too, says Helena Miton, a Complexity Postdoctoral Fellow at the Santa Fe Institute. Although researchers in the field generally acknowledge the influence of the environment on cultural shifts, she says, the effects have never been investigated experimentally.

To tease out those influences, Miton recently designed a series of experiments -- using three identical drums and over 100 participants -- to investigate the influence of material constraints on the development of culture. She and her collaborators described the experiment and their results in Proceedings of the Royal Society B, the Royal Society's primary biology journal.

The group focused in particular on how environmental factors influence the evolution of rhythm. Miton says she chose to study music because instruments clearly depend on material constraints. The materials available to a community, for example, will determine the kinds of instruments they can create, which in turn shape the acoustics and sounds.

"We wanted to have an experiment that was as simple as possible," says Miton. The researchers recruited 120 participants, none of whom had ever studied music, to participate in an experiment modeled on the game "Telephone." Such so-called transmission chains, says Miton, are often used in laboratory settings to mimic cultural communications.

Participants were divided into chains of six people each. The first person listened to a simple sequence of beats played on three drums, and then attempted to replicate the rhythm. The second person listened to the first person's attempt and tried to replicate it, and so on. Miton and her collaborators studied how the rhythms changed through the transmission.

In some chains, people were given a rhythm to play on drums sitting next to each other. Others had to try to recreate beats on drums separated by larger distances. And still others faced a mix of small and large distances between the drums they were using. In total, the researchers studied four different spatial configurations of drums and compared how the rhythms produced by participants diverged across those configurations.

"People transform what they heard in a very systematic, rather than random, way," says cognitive scientist Dan Sperber at Central European University, in Budapest, who worked with Miton on the project. "We can predict how the rhythms will change." The scientists hypothesized, correctly, that over time the rhythms would diverge significantly from the original seed rhythm, and in a specific way for each configuration.

"This was a proof of concept experiment to show that with different environments, different cultural patterns would emerge," says Miton. "What's important is that we showed that you can parse out ecological and psychological factors."

She says she hopes this simple drum-and-telephone experiment will inspire new ways to tease out the many influences on cultural evolution in the future.

Fossils recovered from Antarctica in the 1980s represent the oldest giant members of an extinct group of birds that patrolled the southern oceans with wingspans of up to 21 feet that would dwarf the 11½-foot wingspan of today's largest bird, the wandering albatross.

Called pelagornithids, the birds filled a niche much like that of today's albatrosses and traveled widely over Earth's oceans for at least 60 million years. Though a much smaller pelagornithid fossil dates from 62 million years ago, one of the newly described fossils -- a 50 million-year-old portion of a bird's foot -- shows that the larger pelagornithids arose just after life rebounded from the mass extinction 65 million years ago, when the relatives of birds, the dinosaurs, went extinct. A second pelagornithid fossil, part of a jaw bone, dates from about 40 million years ago.

"Our fossil discovery, with its estimate of a 5-to-6-meter wingspan -- nearly 20 feet -- shows that birds evolved to a truly gigantic size relatively quickly after the extinction of the dinosaurs and ruled over the oceans for millions of years," said Peter Kloess, a graduate student at the University of California, Berkeley.

The last known pelagornithid is from 2.5 million years ago, a time of changing climate as Earth cooled, and the ice ages began.

Kloess is the lead author of a paper describing the fossil that appears this week in the open access journal Scientific Reports. His co-authors are Ashley Poust of the San Diego Natural History Museum and Thomas Stidham of the Institute of Vertebrate Paleontology and Paleoanthropology at the Chinese Academy of Sciences in Beijing. Both Poust and Stidham received their Ph.Ds from UC Berkeley.

Birds with pseudoteeth

Pelagornithids are known as 'bony-toothed' birds because of the bony projections, or struts, on their jaws that resemble sharp-pointed teeth, though they are not true teeth, like those of humans and other mammals. The bony protrusions were covered by a horny material, keratin, which is like our fingernails. Called pseudoteeth, the struts helped the birds snag squid and fish from the sea as they soared for perhaps weeks at a time over much of Earth's oceans.

Large flying animals have periodically appeared on Earth, starting with the pterosaurs that flapped their leathery wings during the dinosaur era and reached wingspans of 33 feet. The pelagornithids came along to claim the wingspan record in the Cenozoic, after the mass extinction, and lived until about 2.5 million years ago. Around that same time, teratorns, now extinct, ruled the skies.

The birds, related to vultures, "evolved wingspans close to what we see in these bony-toothed birds (pelagornithids)," said Poust. "However, in terms of time, teratorns come in second place with their giant size, having evolved 40 million years after these pelagornithids lived. The extreme, giant size of these extinct birds is unsurpassed in ocean habitats,""

The fossils that the paleontologists describe are among many collected in the mid-1980s from Seymour Island, off the northernmost tip of the Antarctic Peninsula, by teams led by UC Riverside paleontologists. These finds were subsequently moved to the UC Museum of Paleontology at UC Berkeley.

Kloess stumbled across the specimens while poking around the collections as a newly arrived graduate student in 2015. He had obtained his master's degree from Cal State-Fullerton with a thesis on coastal marine birds of the Miocene era, between 17 million and 5 million years ago, that was based on specimens he found in museum collections, including those in the UCMP.

"I love going to collections and just finding treasures there," he said. "Somebody has called me a museum rat, and I take that as a badge of honor. I love scurrying around, finding things that people overlook."

Reviewing the original notes by former UC Riverside student Judd Case, now a professor at Eastern Washington University near Spokane, Kloess realized that the fossil foot bone -- a so-called tarsometatarsus -- came from an older geological formation than originally thought. That meant that the fossil was about 50 million years old instead of 40 million years old. It is the largest specimen known for the entire extinct group of pelagornithids.

The other rediscovered fossil, the middle portion of the lower jaw, has parts of its pseudoteeth preserved; they would have been up to 3 cm (1 inch) tall when the bird was alive. The approximately 12-cm (5-inch-) long preserved section of jaw came from a very large skull that would have been up to 60 cm (2 feet) long. Using measurements of the size and spacing of those teeth and analytical comparisons to other fossils of pelagornithids, the authors are able to show that this fragment came from an individual bird as big, if not bigger, than the largest known skeletons of the bony-toothed bird group.

A warm Antarctica was a bird playground

Fifty million years ago, Antarctica had a much warmer climate during the time known as the Eocene and was not the forbidding, icy continent we know today, Stidham noted. Alongside extinct land mammals, like marsupials and distant relatives of sloths and anteaters, a diversity of Antarctic birds occupied the land, sea and air.

The southern oceans were the playground for early penguin species, as well as extinct relatives of living ducks, ostriches, petrels and other bird groups, many of which lived on the islands of the Antarctic Peninsula. The new research documents that these extinct, predatory, large- and giant-sized bony-toothed birds were part of the Antarctic ecosystem for over 10 million years, flying side-by-side over the heads of swimming penguins.

"In a lifestyle likely similar to living albatrosses, the giant extinct pelagornithids, with their very long-pointed wings, would have flown widely over the ancient open seas, which had yet to be dominated by whales and seals, in search of squid, fish and other seafood to catch with their beaks lined with sharp pseudoteeth," said Stidham. "The big ones are nearly twice the size of albatrosses, and these bony-toothed birds would have been formidable predators that evolved to be at the top of their ecosystem."

Museum collections like those in the UCMP, and the people like Kloess, Poust and Stidham to mine them, are key to reconstructing these ancient habitats.

"Collections are vastly important, so making discoveries like this pelagornithid wouldn't have happened if we didn't have these specimens in the public trust, whether at UC Riverside or now at Berkeley," Kloess said. "The fact that they exist for researchers to look at and study has incredible value."

COMMON MUTATION IN PARKINSON'S DISEASE INCREASES CELL CALCIUM, MAY CAUSE BRAIN CELL DEATH

Media Contact: Rachel Butchrbutch1@jhmi.edu

Johns Hopkins Medicine researchers have mapped out the cellular pathway that connects the most common genetic mutation associated with Parkinson's disease to brain cell death. In a new study, they show that the mutation initiates a biological pathway that could target brain cells most susceptible to the patterns of cell death leading to Parkinson's disease symptoms.

"This deep dive into the molecular players in Parkinson's disease may provide some answers to its onset and progression," says Valina Dawson, Ph.D., professor of neurology at the Johns Hopkins University School of Medicine, and director of both the neuroregeneration and stem cell programs at the medical school's Institute for Cell Engineering.

The study, published Oct. 1, 2020, in the journal Cell Stem Cell, revealed that a mutation in the leucine-rich repeat kinase 2 (LRRK2) gene shifts the balance of protein production within brain cells, allowing calcium to accumulate inside them. Though mutations in LRRK2 are the most common indicators of inherited Parkinson's disease, their functions within cells are not well understood.

Dawson and her research team learned that a specific mutation within the LRRK2 gene, called Gly2019Ser, or G2019S, produces a protein that becomes more active than normal. They found that this increased activity changes how ribosomes, the protein-making factories of the cell, select which RNA molecules are used to make other proteins. Ribosomes affected by the mutated LRRK2 protein prefer some RNAs with more complex structures than other simple RNAs.

"This preference causes major problems down the line, because it may shift the levels of proteins whose precise regulation is essential for neurons to function and survive," explains Dawson.

Among the consequences, says Dawson, is the regulation of many cell structures that are responsible for maintaining healthy levels of calcium. One such affected structure is the voltage-gated calcium ion channel, a portal crucial for processing and sending biochemical messages across the brain. Previous studies established that too much calcium in a brain cell can cause it to die. Excess calcium also has been linked as a contributing factor to Alzheimer's disease.

"Mapping out this progression of events is an important advancement in understanding the disease and provides more information on how Parkinson's disease may initially arise," says Dawson.

The research team hopes its findings provide opportunities to create new therapies for Parkinson's disease. "Defining each step in the pathway linking the LRRK2 mutation and brain cell death represents a potential target for drug interaction," says Dawson.

BETTER REPAIRED NERVE INSULATION MAY LEAD TO NEW MULTIPLE SCLEROSIS TREATMENTS

Media Contact: Vanessa McMains, Ph.D.vmcmain1@jhmi.edu

In a new study using mice, Johns Hopkins Medicine researchers have found a better way than natural healing to repair damaged insulation surrounding nerve cells. Normally, the natural healing process adds bumps to the surface of the protective fatty sheath, known as myelin, each time it's repaired. Over time and after cumulative damage, the myelin ultimately becomes too misshapen to wrap cleanly around the nerve, causing it to lose function.

This happens in multiple sclerosis (MS), a disorder in which the body's immune system mistakenly attacks the myelin around nerves, shutting them down and causing communication problems between the brain and the rest of the body.

In their study published on Oct. 2, 2020, in Science Advances, the researchers say that using certain drugs may prevent relapsing-remitting MS, the intermittent form of the disorder, from becoming progressive MS -- a chronic form of the condition in which the myelin can no longer repair itself.

"Suppressing the immune system has worked to treat relapsing-remitting MS, but it doesn't protect from the eventual advancement to progressive MS, for which there aren't any good treatments on the market," says Norman Haughey, Ph.D., professor of neurology at the Johns Hopkins University School of Medicine. "We think these findings are a big step toward improving the quality and composition of myelin following a flare-up."

In earlier work by Haughey's team, the researchers looked at the composition of the myelin surrounding nerves found near injured brain tissue taken from deceased people with MS. Myelin is made mostly from hundreds of types of fat molecules and proteins. The researchers saw that myelin around nerves near injury sites looked misshapen compared with that of other nerves, along with having much higher levels of ceramide -- a particular type of fat molecule -- and lower levels of another fat molecule called sulfatide.

Having the correct amount of ceramide is especially important because this fat regulates the curvature of myelin -- too much ceramide and it can't wrap tightly around the nerve, creating "bumps" in the myelin.

In the new study, the researchers fed the drug cuprizone to mice for 26 days to damage the myelin on their nerve cells. The myelin repaired itself, but looked it bumpy and wrapped poorly around the nerve because of the excess ceramide. In a series of experiments, the researchers found that brain inflammation activates the enzyme, neutral sphingomyelinase-2, which produces ceramide.

Working with an expert drug development team led by Barbara Slusher, Ph.D., M.A.S., professor of neurology at the Johns Hopkins University School of Medicine, the researchers identified the small molecular size drug, cambinol, which blocks neutral sphingomyelinase-2 from working. They theorized that this would prevent excess ceramide from being made and incorporated into regenerated myelin after an injury.

After nearly a month of feeding their mice cuprizone to cause myelin damage, the researchers injected them with cambinol. When the myelin grew back this time, it wrapped tightly around the neurons and looked like it did before the damage.

The researchers say this intervention did not completely restore the fat composition of myelin, but it appeared to increase the stability of the myelin, which likely would better protect the underlying neurons.

The team needs to determine if there are impacts from other abnormal fat levels in the repaired myelin even with the prevention of excess ceramide buildup. Also, the researchers need to confirm that the myelin -- after being in its correct shape and structure -- functions as it should and is more stable over long periods of time.

Once this is done, the team hopes to develop small molecular-size inhibitors of neutral sphingomyelinase-2 for eventual use in human trials.

Postdoctoral fellow Seung-Wan Yoo, Ph.D., M.S., is the lead author of this study.

Scientists at Fred Hutchinson Cancer Research Center in Seattle have shown that a potent antibody from a COVID-19 survivor interferes with a key feature on the surface of the coronavirus's distinctive spikes and induces critical pieces of those spikes to break off in the process.

The antibody -- a tiny, Y-shaped protein that is one of the body's premier weapons against pathogens including viruses -- was isolated by the Fred Hutch team from a blood sample received from a Washington state patient in the early days of the pandemic.

The team led by Drs. Leo Stamatatos, Andrew McGuire and Marie Pancera previously reported that, among dozens of different antibodies generated naturally by the patient, this one -- dubbed CV30 -- was 530 times more potent than any of its competitors.

Using tools derived from high-energy physics, Hutch structural biologist Pancera and her postdoctoral fellow Dr. Nicholas Hurlburt have now mapped the molecular structure of CV30. They and their colleagues published their results online today in the journal Nature Communications.

The product of their research is a set of computer-generated 3D images that look to the untrained eye as an unruly mass of noodles. But to scientists they show the precise shapes of proteins comprising critical surface structures of antibodies, the coronavirus spike and the spike's binding site on human cells. The models depict how these structures can fit together like pieces of a 3D puzzle.

"Our study shows that this antibody neutralizes the virus with two mechanisms. One is that it overlaps the virus's target site on human cells, the other is that it induces shedding or dissociation of part of the spike from the rest," Pancera said.

On the surface of the complex structure of the antibody is a spot on the tips of each of its floppy, Y-shaped arms. This infinitesimally small patch of molecules can neatly stretch across a spot on the coronavirus spike, a site that otherwise works like a grappling hook to grab onto a docking site on human cells.

The target for those hooks is the ACE2 receptor, a protein found on the surfaces of cells that line human lung tissues and blood vessels. But if CV30 antibodies cover those hooks, the coronavirus cannot dock easily with the ACE2 receptor. Its ability to infect cells is blunted.

This very effective antibody not only jams the business end of the coronavirus spike, it apparently causes a section of that spike, known as S1, to shear off. Hutch researcher McGuire and his laboratory team performed an experiment showing that, in the presence of this antibody, there is reduction of antibody binding over time, suggesting the S1 section was shed from the spike surface.

The S1 protein plays a crucial role in helping the coronavirus to enter cells. Research indicates that after the spike makes initial contact with the ACE2 receptor, the S1 protein swings like a gate to help the virus fuse with the captured cell surface and slip inside. Once within a cell, the virus hijacks components of its gene and protein-making machinery to make multiple copies of itself that are ultimately released to infect other target cells.

The incredibly small size of antibodies is difficult to comprehend. These proteins are so small they would appear to swarm like mosquitos around a virus whose structure can only be seen using the most powerful of microscopes. The tiny molecular features Pancera's team focused on the tips of the antibody protein are measured in nanometers -- billionths of a meter.

Yet structural biologists equipped with the right tools can now build accurate 3D images of these proteins, deduce how parts of these structures fit like puzzle pieces, and even animate their interactions.

Fred Hutch structural biologists developed 3D images of an antibody fished from the blood of an early COVID-19 survivor that efficiently neutralized the coronavirus.

Dr. Nicholas Hurlburt, who helped develop the images, narrates this short video showing how that antibody interacts with the notorious spikes of the coronavirus, blocking their ability to bind to a receptor on human cells that otherwise presents a doorway to infection.

Key to building models of these nanoscale proteins is the use of X-ray crystallography. Structural biologists determine the shapes of proteins by illuminating frozen, crystalized samples of these molecules with extremely powerful X-rays. The most powerful X-rays come from a gigantic instrument known as a synchrotron light source. Born from atom-smashing experiments dating back to the 1930s, a synchrotron is a ring of massively powerful magnets that are used to accelerate a stream of electrons around a circular track at close to the speed of light. Synchrotrons are so costly that only governments can build and operate them. There are only 40 of them in the world.

Pancera's work used the Advanced Photon Source, a synchrotron at Argonne National Laboratory near Chicago, which is run by the University of Chicago and the U.S. Department of Energy. Argonne's ring is 1,200 feet in diameter and sits on an 80-acre site.

As the electrons whiz around the synchrotron ring, they give off enormously powerful X-rays -- far brighter than the sun but delivered in flashes of beams smaller than a pinpoint.

Structural biologists from around the world rely on these brilliant X-ray beamlines to illuminate frozen crystals of proteins. They reveal their structure in the way these bright beams are bent as they pass though the molecules. It takes powerful computers to translate the data readout from these synchrotron experiments into the images of proteins that are eventually completed by structural biologists.

The Fred Hutch team's work on CV30 builds on that of other structural biologists who are studying a growing family of potent neutralizing antibodies against the coronavirus. The goal of most coronavirus vaccine candidates is to stimulate and train the immune system to make similar neutralizing antibodies, which can recognize the virus as an invader and stop COVID-19 infections before they can take hold.

Neutralizing antibodies from the blood of recovered COVID-19 patients may also be infused into infected patients -- an experimental approach known as convalescent plasma therapy. The donated plasma contains a wide variety of different antibodies of varying potency. Although once thought promising, recent studies have cast doubt on its effectiveness.

However, pharmaceutical companies are experimenting with combinations of potent neutralizing antibodies that can be grown in a laboratory. These "monoclonal antibody cocktails" can be produced at industrial scale for delivery by infusion to infected patients or given as prophylactic drugs to prevent infection. After coming down with COVID-19, President Trump received an experimental monoclonal antibody drug being tested in clinical trials by the biotech company Regeneron, and he attributes his apparently quick recovery to the advanced medical treatment he received.

The Fred Hutch research team holds out hope that the protein they discovered, CV30, may prove to be useful in the prevention or treatment of COVID-19. To find out, this antibody, along with other candidate proteins their team is studying, need to be tested preclinically and then in human trials.

"It is too early to tell how good they might be," Pancera said.

In the world of rare genetic diseases, exome and genome sequencing are two powerful tools used to make a diagnosis. A recent addition to the toolkit, RNA sequencing, has been demonstrated to help researchers narrow down disease candidate variants identified first on exome and genome sequencing. A new study from Baylor College of Medicine finds that starting genetic analysis with RNA sequencing can increase diagnostic yield even further. The results are published in the Journal of Clinical Investigation.

Baylor has been a leader in developing clinical applications of exome and genome sequencing, a technique that is now being used in clinics worldwide. Researchers at the National Institutes of Health (NIH) Undiagnosed Diseases Network (UDN) have successfully used exome and genome sequencing to increase the diagnostic rate of rare genetic diseases to about 35%.

"That's impressive because these cases have already had such an extensive workup already," said Dr. Brendan Lee, corresponding author on the study and professor and chair of molecular and human genetics at Baylor. "The 35% diagnostic rate is great, but unfortunately that means there's still 65% that remain undiagnosed."

Exome and genome sequencing do have limits. Over the years, scientists have identified about 4,000 disease-causing genes and 7,000 associated distinct clinical diseases, but relatively little is known about the roughly 16,000 other genes in the genome. Further, only about 1 or 2% of the genome is coding, meaning it is translated into RNA and proteins. Researchers are limited in their ability to interpret genetic changes in the noncoding regions of the genome.

"When a patient's exome and genome is sequenced, we interpret the results and come up with a list of gene mutations that could cause a disease," said Lee, the Robert and Janice McNair Endowed Chair in Molecular and Human Genetics at Baylor. "Often, we can't assign a definitive effect to many DNA mutations because there's not enough information."

To assist in interpretation of exome and genome sequencing, the UDN has increasingly turned to RNA sequencing. While exome and genome sequencing identify genetic changes in the DNA, RNA sequencing can reveal the effects of those changes, for example if a gene has lower expression than expected. RNA sequencing can also tell us about the effects of noncoding changes, something that is very important as we transition from exome to genome sequencing.

Trying a new approach

RNA sequencing has been used as a secondary tool to help prioritize disease gene candidates identified with exome and genome sequencing, and it has been shown to increase diagnostic yield to variable degrees. The Baylor team wanted to try a different approach with the UDN cases. Using a novel pipeline developed with collaborators in Germany, they started with the RNA sequencing to first identify unique differences in gene expression and splicing. Researchers could then trace the problem back to a corresponding genetic change in the exome and genome sequencing data.

"This strategy really flips the way we normally approach a case, looking at the end result in the RNA and working backwards to find the cause in the exome or genome. It allows biology to tell us where to look to make a diagnosis," said Dr. David Murdock, lead author of the study and assistant professor of molecular and human genetics at Baylor.

"We found this RNA sequencing first approach was extremely powerful," Lee said. "It was able to very rapidly point at the gene we should look at. Moreover, it did so in cases in which we would not have been able to identify the disease gene candidate using exome and genome sequencing alone. If we had used the old way and generated a priority candidate list, these gene mutations would not have even been in the priority list."

Increased diagnostic yield

The team found that exome and genome sequencing sometimes missed small deletions in genes. However, the RNA sequencing data showed that these deletions could dramatically affect gene expression. RNA sequencing also picked up changes in expression and splicing caused by variants in noncoding regions that would not have been flagged in regular exome and genome sequencing.

"We see lots of changes in the noncoding region, and there's no way to know if they're important," Lee said. "But the RNA sequencing will show an 80% decrease in expression related to that gene, and then we can assign causality to that noncoding variant."

The Baylor study found that beginning with RNA sequencing could increase the diagnostic yield 17% from the traditional exome and genome sequencing approach, bringing their overall diagnosis rate to roughly 50%. As part of the study, researchers analyzed both skin cells and blood cells and found that skin cells were more informative in diagnosis because of their homogenous nature and better gene expression.

"I see RNA sequencing with this approach as eventually becoming standard practice, especially as we move more from exome to genome sequencing. It allows us to diagnose so many more patients and gives families the answer they've been seeking," Murdock said.

"A diagnosis is not black and white. It involves variable amounts of certainty," Lee said. "The availability of this tool will change the certainty level, improving diagnostic yield and increasing confidence in that diagnosis."

Genetic factors that reduce the placenta's capacity to protect the fetus from the zika virus are described by Brazilian researchers in an article published in PLOS Neglected Tropical Diseases. According to the authors, the findings help explain why only some babies whose mothers are infected by zika virus during pregnancy are born with some kind of anomaly.

Since the 2015 epidemic at least 3,500 babies have suffered from zika congenital syndrome, which includes microcephaly, brain calcifications, and auditory and visual deficits, according to statistics available from the Brazilian Health Ministry. However, these cases are believed to correspond to between 5% and 10% of all the fetuses exposed to zika in the first trimester, the riskiest period of pregnancy.

"We observed differences in the expression of two classes of genes in the placenta of the affected babies. One is associated with the placenta's capacity to invade and attach to the wall of the uterus. The other has to do with the production of certain molecules known as chemokines, which attract maternal immune cells to combat the virus in the placental barrier," said Sergio Verjovski , a professor in the University of São Paulo's Chemistry Institute (IQ-USP) and principal investigator for the study, which was supported by São Paulo Research Foundation - FAPESP .

The discovery was only possible thanks to a cellular reprogramming technique that enabled the researchers to recreate in the laboratory the cells that make up the so-called primitive placenta, which gives the fetus support in the first trimester.

These cells, called trophoblasts, were obtained from blood samples donated by three pairs of discordant twins - cases in which only one sibling was born with microcephaly although both were equally exposed to viral infection in the womb.

Because these children represent an ideal model for the study of genetic factors that increase susceptibility to congenital zika syndrome, they have been monitored for about four years by researchers affiliated with the Human Genome and Stem-Cell Research Center (HUG-CELL), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP. HUG-CELL's principal investigator is Mayana Zatz , a professor in the University of São Paulo's Bio-Science Institute (IB-USP) and a co-author of the article.

"First we reprogrammed the blood cells so that they returned to a stage of pluripotency similar to that of embryo stem cells," Verjovski said. "Then we had these induced pluripotent stem cells [IPSCs] differentiate in vitro into primitive trophoblasts."

Next, two groups of placental cells were cultured, one to simulate the primitive placenta of babies born with microcephaly and hence most affected by zika, and the other to represent the placenta of twins resistant to viral infection.

All the cultured cells were infected with a Brazilian strain of the virus (ZIKV-BR), which circulated here during the 2015-16 epidemic. The researchers then used sequencing techniques to compare the two groups' transcriptomes (all RNA molecules expressed by their genes). The aim was to see in each case how the virus affected gene expression in placental cells.

"In the trophoblasts of the babies born with microcephaly, we observed decreased expression of several genes associated with the extracellular matrix. These genes are a key part of a process whereby the placenta, which is fetal tissue, invades and attaches to the uterus," Verjovski said. "This process is important for the placenta to nourish the fetus properly and act as a physical barrier against pathogens and toxins."

Analysis conducted 48 and 96 hours after infection showed statistically significant growth of chemokines RANTES/CCL5 (up to 4.6 times) and IP10 (up to 96 times) only in the trophoblasts from the resistant babies.

"These molecules are important signalers to the mother's immune defense in the placental barrier. They attract to the site maternal cells capable of destroying the virus," Verjovski said.

The results, therefore, suggest that the primitive placenta in resistant babies is able to prevent infection of fetal tissue more effectively.

"We would need to perform new experiments to confirm this hypothesis," Verjovski said. "One possibility would be placing the trophoblasts infected with zika in contact with blood samples from pregnant women, and observing whether placental cells of resistant babies are indeed able to attract more of the mother's immune cells. However, this isn't easy to do: we would need to obtain blood samples from pregnant women whose immune cells were compatible with the discordant twins' cells."

In any event, he continued, the identification of genes differentially expressed in babies with microcephaly paves the way for research that aims to develop interventions capable of preventing damage to the fetus by the virus. "We think it would be more feasible to develop a treatment that reinforces the placental barrier and prevents infection of the fetus than to invest, for example, in a drug that blocks damage by the virus directly in the fetal nervous system," he said.

More than genetics

In a study published in 2017 in PNAS, Verjovski and collaborators at the University of Missouri in the United States showed that the primitive placenta offers a far more favorable environment to infection by zika than the mature placenta because of increased first-trimester expression of several genes that encode attachment proteins that facilitate viral entry into fetal tissue. On the other hand, the mature placenta expresses more proteins associated with antiviral defense. This study involved primitive and mature trophoblasts also obtained by cellular reprogramming, but from embryonic stem cells (and hence not from children exposed to the virus during pregnancy).

"At the time we raised the hypothesis that the primitive placenta in fetuses susceptible to zika expressed more attachment receptors so that these babies were exposed to a higher viral load. We've now refuted this theory with the new findings," Verjovski said.

The latest study showed, he added, that gene expression is initially the same in trophoblasts from twins born with and without microcephaly, but becomes different after viral infection. "For some unknown reason, the placenta responds differently to viral cell entry in susceptible and resistant babies," he said.

Other genetic factors associated with greater susceptibility to zika congenital syndrome were described by the HUG-CELL team in an article published in 2018 in Nature Communications . The researchers showed that zika replicated much more in neural progenitor cells (NPCs) from babies with microcephaly than in NPCs from their resistant siblings. Furthermore, NPCs from susceptible babies proliferated less and died more than NPCs from resistant babies. In this case, the NPCs were also generated by cellular reprogramming from blood samples donated by discordant twins.

A comparison of gene expression in the two groups brought to light differences in two important signaling pathways for brain development during the embryonic period - one mediated by the protein mTOR and the other by Wnt. These pathways regulate the proliferation and migration of central nervous system cells, among other things (read more at: agencia.fapesp.br/27084).

Other factors that have been associated with a heightened risk of fetal anomalies besides genetics include maternal diet, gut microbiota composition, and maternal exposure to pollutants and other pathogens. One of the questions that remain open is why in some regions, such as the Northeast of Brazil, zika caused many more cases of microcephaly than in others where zika outbreaks also occurred.

"In the study published in 2017, we compared two different zika strains - one isolated in Uganda [in Africa, where the virus originated] and another in Polynesia. The Brazilian strain derived from the latter," Verjovski said. "We found the African strain to be far more virulent in the primitive placenta. It's possible therefore that no cases of microcephaly occurred in Africa because the pregnant women infected there miscarried and the virus became less destructive as it mutated so that it was able to replicate for longer in the fetus and a larger number of infected women were able to take their pregnancies to term."

Throughout the pandemic, healthcare workers have seen more than just the lungs affected by COVID-19. Doctors have reported neurological complications including stroke, headache and seizures, but the information is limited to a number of individual reports that are not reflective of a larger population.

Researchers from Baylor College of Medicine and the University of Pittsburgh have gathered more than 80 studies, reviewed the data, and identified commonalities that are helping to paint a broader picture of how COVID-19 affects the brain.

The findings, published in Seizure: European Journal of Epilepsy, focused on electroencephalogram (EEG) abnormalities of the brain. EEG is a test used to evaluate the electrical activity in the brain. Researchers found that about one-third of patients who were given an EEG had abnormal neuroimaging localized in the frontal lobe of the brain.

"We found more than 600 patients that were affected in this way. Before, when we saw this in small groups we weren't sure if this was just a coincidence, but now we can confidently say there is a connection," said Dr. Zulfi Haneef, assistant professor of neurology/neurophysiology at Baylor.

The main reason a patient would be given an EEG is if altered mentation is noted, meaning a patient might have a slowed reaction to stimuli, followed by seizure-like events, speech issues, confusion or inability to wake up after sedation. The most common findings from the EEG were slowing or abnormal electrical discharge, mostly in the frontal lobe.

Some of the EEG alterations found in COVID-19 patients may indicate damage to the brain that might not be able to be repaired after recovering from the disease.

"As we know, the brain is an organ that cannot regenerate, so if you have any damage it will more than likely be permanent or you will not fully recover," Haneef said.

Haneef found the location of the abnormal activity interesting.

"We know that the most likely entry point for the virus is the nose, so there seems to be a connection between the part of the brain that is located directly next to that entry point," he said. "Another interesting observation was that the average age of those affected was 61, one-third were female and two-thirds were males. This suggests that brain involvement in COVID-19 could be more common in older males. More research is needed but these findings show us these are areas to focus on as we move forward."

It may not always be the virus acting directly on the brain causing the abnormal EEG readings, Haneef said. It could be the oxygen intake, heart problems related to COVID-19 or another type of side effect, which is why he says that comprehensive patient care should include more imaging of the brain or EEG testing as necessary.

"These findings tell us that we need to try EEG on a wider range of patients, as well as other types of brain imaging, such as MRI or CT scans, that will give us a closer look at the frontal lobe," Haneef said. "A lot of people think they will get the illness, get well and everything will go back to normal, but these findings tell us that there might be long-term issues, which is something we have suspected and now we are finding more evidence to back that up."

Researchers at UPF, the National Centre for Cardiovascular Research, ICREA and Ciberned have identified a physiological mechanism that maintains the regenerative capacity of muscle stem cells, and surprisingly resists the passage of time far more than expected, until geriatric age. This study presents the results of more than seven years of research and collaborations with several laboratories in Europe and the US.

Skeletal muscle regeneration depends on a muscle stem cell population (satellite cells) in a dormant or quiescent state, a situation that can be triggered by damage or stress to form new muscle fibres and expand in new stem cells.

The regenerative functions of these stem cells are known to decline with ageing. Dr. Pura Muñoz-Cánoves, the ICREA professor who leads the Cell Biology research group of the Department of Experimental and Health Sciences (DCEXS) at Pompeu Fabra University (UPF) in Barcelona, and head of the Tissue Regeneration Group of the National Centre for Cardiovascular Research (CNIC) in Madrid, and of Ciberned, and colleagues, have found in experiments with mice that all muscle stem cells, despite being quiescent, are not equal, and have identified a subgroup that maintains its regenerative capacity over time, declining only at geriatric age.

The researchers have shown that this subgroup of quiescent stem cells has a greater regenerative capacity through the activation of the FoxO signalling pathway (previously associated with longevity), which maintains the expression of a youthful gene programme throughout life; however, at geriatric age, FoxO activation in this subgroup of cells is lost, causing their loss of functionality.

According to the results presented in Nature Cell Biology, compounds that activate FoxO may have a rejuvenating effect on aged muscle stem cells, opening the way to improve the health of elderly people who are debilitated by the loss of muscle mass. It may also be useful for persons who have lost muscle mass as a result of neuromuscular diseases or effects associated with cancer or infectious or inflammatory diseases.

The body's immune system defeats diseases by sensing foreign invaders, like bacteria or viruses, and then mounting a response against them.

But just how immune cell receptors work together to sense multiple molecules and make these decisions remained a mystery. Now, researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago have discovered a general property for understanding how these cells sense and respond to microbial signals.

By studying how molecules impact immune cells, they found that while the effect of a single molecule does not predict the effect of two molecules together, the complexity stops there. In fact, the effect of singles and pairs of molecules can be used to predict how triplets of molecules work.

The result, led by Asst. Prof. Nicolas Chevrier and published October 27 in the journal Cell Systems, led to a more effective cancer immunotherapy in mice and could lead to more effective vaccines for both existing and novel viruses.

Key to designing vaccines

Each of the body's innate immune cells has receptors that recognize molecules from foreign pathogens. To fight off bacteria or viruses, those cells make decisions in response to complex combinations of inputs from those molecules. Though researchers have studied singular pathways, how these pathways work together is still not well understood.

Chevrier and his collaborators set out to better understand how cells integrate multiple signals into a response. Not only would it help answer a basic fundamental question of biology, it would also help design vaccines that use adjuvants, molecules that help modulate the immune system and enhance its response.

Though just a few vaccines currently use them, adjuvants might be the key to developing new kinds of vaccines. Right now, FDA-approved adjuvants target only one or two of the cell's receptors. If researchers could find the right combination to target more, vaccines could become more effective.

Understanding how combinations work together

Chevrier and his collaborators used adjuvants to stimulate immune cells in petri dishes to figure out what happens when single molecules, pairs of molecules, and triplets of molecules are used. If the results were additive, the effects of one molecule and the effects of another molecule would, when combined, remain the same. Researchers found that wasn't the case - two molecules combined together led to different effects than each had singularly.

But they did find that the effect of single molecules and pairs of molecules could accurately predict what happened with triplets of molecules.

"It could have been infinitely complex, but it's not," Chevrier said. "We are the first to show you can predict higher-order effects across immune pathways with very simple models."

Model used to design cancer immunotherapy

To prove their theory, the researchers injected cells conditioned with certain combinations of adjuvants - creating a specific cancer immunotherapy treatment - in a mouse model with tumors. The response was potent: the tumors grew five to ten times less in treated mice versus untreated mice.

"That was very encouraging," Chevrier. "Now we need to better understand the mechanisms of why this worked so well."

The researchers also hope to search for new combinations of adjuvants that have equally strong effects and eventually mount a clinical trial in humans.

"Now that we can predict the effects of multiple adjuvants with little data and a simple model, we need to extend this knowledge to the design of vaccines against both new and old threats," Chevrier said.

To better understand how the novel coronavirus behaves and how it can be stopped, scientists have completed a three-dimensional map that reveals the location of every atom in an enzyme molecule critical to SARS-CoV-2 reproduction.

Researchers at the Department of Energy's Oak Ridge National Laboratory used neutron scattering to identify key information to improve the effectiveness of drug inhibitors designed to block the virus's replication mechanism. The research is published in the Journal of Biological Chemistry.

The SARS-CoV-2 virus, which causes the COVID-19 disease, expresses long chains of proteins composed of approximately 1,900 amino acid residues. For the virus to reproduce, those chains have to be broken down and cut into smaller strands by an enzyme called the main protease. The active protease enzyme is formed from two identical protein molecules held together by hydrogen bonds. Developing a drug that inhibits or blocks the protease activity will prevent the virus from replicating and spreading to other cells in the body.

"This new information is exactly what is needed to design inhibitors with a higher degree of specificity, ensuring the inhibitor molecules are binding very tightly to their intended targets and disabling the protease," said ORNL's Andrey Kovalevsky, corresponding author.

Neutron experiments first revealed that the site containing the amino acids where the protein chains are cut is in an electrically charged reactive state and not in a resting or neutral state, contrary to previously held beliefs. Second, they mapped the location of each hydrogen atom in the places where inhibitors would bind to the protease enzyme, as well as the electrical charges of the associated amino acids. The experiments also charted the entire network of hydrogen bonds between the protein molecules that hold the enzyme together and enable it to initiate the chemical process of cutting the protein chains.

"Half of the atoms in proteins are hydrogen. Those atoms are key players in enzymatic function and are essential to how drugs bind," Kovalevsky said. "If we don't know where those hydrogens are and how the electrical charges are distributed inside the protein, we can't design effective inhibitors for the enzyme."

The team's neutron study builds on previous research published in the journal Nature Communications, creating a complete atomic structure of the protease enzyme. The researchers have also made their data publicly available to the scientific community before both papers were published to accelerate solutions to the global pandemic.

Neutrons are ideal probes for studying biological structures because they are nondestructive and highly sensitive to light elements such as hydrogen. The neutron scattering experiments were performed at the High Flux Isotope Reactor and the Spallation Neutron Source at ORNL. The protein samples were synthesized in adjacent facilities at the Center for Structural Molecular Biology.

"This might be the quickest neutron structure of a protein ever produced. We started neutron experiments in May, and within five months, we obtained and published our results. That's something that usually takes years," said ORNL corresponding author Leighton Coates. "This work demonstrates what we can do at Oak Ridge. Everything was done here from start to finish. The proteins were expressed, purified, and crystallized, and all the data was collected and analyzed on site -- a completely vertically integrated approach."

The team will now use the newly obtained information to investigate the binding properties of drug molecule candidates to produce improved COVID-19 therapeutics.

"Not only is this the first time anyone has obtained a neutron structure of a coronavirus protein, but it's also the first time anyone has looked at this class of protease enzymes using neutrons," said ORNL's Daniel Kneller, the study's first author. "It's an outstanding example of neutron crystallography serving the community when it needs it the most."

Cucurbit downy mildew is a devastating disease for the United States cucurbit industry, which includes cucumbers, watermelon, squash, and pumpkin. The disease has caused major losses in North Carolina, which has significant cucumber and watermelon acreage. To help growers better manage this disease, a group of plant pathologists at North Carolina State University sought to better understand the biology of the pathogen that causes downy mildew.

They determined that the causal pathogen, Pseudoperonospora cubensis, has two genetically distinct host-adapted clades and also found that wild cucurbits can serve as reservoirs for this pathogen. Clade 1 isolates more frequently infect squash, pumpkin, and watermelon while clade 2 impacted cucumber and cantaloupe. They also found that evidence of recombination in clade 1 isolates but not clade 2 isolates.

"Overall, our findings have important implications for disease management because clade-specific factors such as host susceptibility and inoculum availability of each clade by region may influence pathogen outbreaks in different commercial cucurbits, timing of fungicide applications, and phenotyping for host resistance breeding efforts," explained lead author Emma Wallace.

"It was surprising to us to find two host-adapted clades with such distinct genetic differentiation and only one clade showing evidence of recombination. We were also surprised that wild cucurbits can become readily infected by one or both clades, especially since some of those wild cucurbits are widespread in the United States and some are perennial," added co-author Kimberly D'Arcangelo.

While previous research had shown evidence of two subpopulations within the pathogen, none were able to identify the main factors underlying those populations due to sampling limitations. Using a population genetics approach, Wallace and her colleagues applied a robust and standardized sampling strategy to investigate P. cubensis populations that infect wild cucurbit hosts.

"Our findings will have significant impacts on the adoption of crop-specific management practices," said corresponding author Lina Quesada. "Current disease management recommendations are provided under the assumption that P. cubensis isolates were somewhat uniform. However, this paper and related projects have revealed that the two clades can have important biological differences, such as host preference, that are relevant when thinking about how to manage disease."

Moving forward, plant pathologists will have to provide crop-specific recommendations as opposed to using the same approach for all cucurbit crops infected with downy mildew. For more information, read "Population Analyses Reveal Two Host-Adapted Clades of Pseudoperonospora cubensis, the Causal Agent of Cucurbit Downy Mildew, on Commercial and Wild Cucurbits" published in the September issue of Phytopathology.

Four in 10 people with advanced multiple sclerosis, or MS, are emotionally abused by someone responsible for caring for them, reports a study led by the University of California, Riverside.

Further, the study finds one quarter are financially exploited, one in six are neglected, one in nine are battered, and one in 12 are sexually assaulted by a caregiver.

"We knew we would find some level of abuse and neglect, but we were surprised by how prevalent it is," said Dr. Elizabeth Morrison-Banks, a health sciences clinical professor at the UC Riverside School of Medicine, who led the study. "The findings of this study represent a collective cry for help from so many families affected by multiple sclerosis across the United States."

MS is an autoimmune disease that affects more than 2.3 million people worldwide. This chronic, degenerative neurological condition periodically shutters communication between the brain and other parts of the body, resulting in symptoms that include numbness and tingling in the arms and legs, as well as blindness and paralysis.

"MS affects people in different ways," Morrison-Banks said. "Some people live with MS for many years but with milder symptoms, and they may remain completely self-sufficient and never require a caregiver. Others are less fortunate and develop neurological disability that can make them vulnerable to abuse and neglect if they are unable to move around independently, take care of their own finances, or get away from the situation when family conflict escalates. These problems are compounded if the person with MS and family lack financial resources."

Morrison-Banks explained that for families who are struggling economically, relying on a paid caregiver is often not an option, and family caregivers have to step in to fill the breach.

"Some family caregivers are also working full time, caring for children or other family members, and sometimes dealing with health issues of their own," she said. "All of these challenges can increase risk of mistreatment. I want to emphasize that the majority of family caregivers do not mistreat those they care for, even in situations that can be very challenging. Nonetheless, it is important to recognize the risk factors for mistreatment of people with disabilities, and do what we can to identify, mitigate, and prevent abuse and neglect."

Study results appear in Multiple Sclerosis and Related Disorders. According to Morrison-Banks and her colleagues, the research paper is the first published survey documenting the nature and extent of caregiver mistreatment of adults with MS in the United States. The research team collaborated with the North American Research Committee on Multiple Sclerosis to conduct a telephone survey of 206 American adults with advanced MS living across the United States.

The preliminary study found nearly 55% of respondents disclosed undergoing some form of mistreatment since they started receiving care from a family member or friend.

The researchers do not fully understand all the risk factors for mistreatment. Their anonymous telephone survey did find, however, that family members who had to be the primary caregiver every day, day in and day out, were at higher risk of mistreating the person with MS. Other risk factors included the person with MS having higher levels of cognitive impairment or fatigue, the caregiver having a mental health diagnosis, alcohol use by the caregiver or by the person with MS, and lower levels of social support within the family.

As a MS specialist at UCR Health, Morrison-Banks has worked for years with many families affected by MS.

"Being a full-time family caregiver for someone with substantial neurological disability often presents significant challenges," she said. "Many families take these challenges in stride, but others end up in situations of abuse and/or neglect."

The researchers were surprised to find no published studies documenting how many people with MS have experienced mistreatment.

"We all felt it was important to study this topic in order to help families dealing with advanced MS," Morrison-Banks said, adding the first step toward addressing the problem is to recognize that people with MS are at high risk of mistreatment.

Community service organizations such as the National Multiple Sclerosis Society, the Multiple Sclerosis Association of America, and in Riverside County a local organization called Act for MS provide support and services for families in need.

"Our study is a good reminder for all that mistreatment is occurring out there for people with MS and other disabling conditions," Morrison-Banks said. "Health care professionals should maintain a high index of suspicion. We can't assume that all people with advanced MS are living in safe situations, even if they don't bring up their concerns on their own."

The study did not include paid caregivers or trained clinicians. A study of paid caregivers is an important next step for the researchers, requiring different methods for data collection. Morrison-Banks's team would study mistreatment involving paid caregivers, including those working in nursing facilities and other institutions. Another important area for future research for the team is to study the effectiveness of interventions to detect and prevent abuse and neglect of people living with advanced multiple sclerosis.

NEW YORK, NY (Oct. 27, 2020)--Coronaviruses are adept at imitating human immune proteins that have been implicated in severe COVID-19 disease, a study from researchers at Columbia University Vagelos College of Physicians and Surgeons has found.

The study was published online ahead of print in Cell Systems.

Many plants and animals use the art of mimicry to trick their prey or predators. Viruses employ a similar strategy: Viral proteins can mimic the three-dimensional shapes of their host's proteins to trick the host into helping the virus complete its life cycle.

"Viruses use mimicry for the same reason as plants and animals--deception," says Sagi Shapira, PhD, assistant professor of systems biology at Columbia University Vagelos College of Physicians and Surgeons. "We hypothesized that identifying viral-protein look-alikes would give us clues to the way viruses--including SARS-CoV-2--cause disease."

Coronaviruses Are Masters of Mimicry

In the study, Shapira used supercomputers to search for viral mimics with a program similar to 3D facial recognition software. They scanned more than 7,000 viruses and over 4,000 hosts across Earth's ecosystems and uncovered 6 million instances of viral mimicry.

"Mimicry is a more pervasive strategy among viruses than we ever imagined," Shapira says. "It's used by all kinds of viruses, regardless of the size of the viral genome, how the virus replicates, or whether the virus infects bacteria, plants, insects or people."

But some types of viruses used mimicry more than others. Papilloma and retroviruses, not so much. Coronaviruses, on the other hand, are particularly good at it and were found to mimic over 150 proteins, including many that control blood coagulation or activate complement--a set of immune proteins that help target pathogens for destruction and increase inflammation in the body.

"We thought that by mimicking the body's immune complement and coagulation proteins, coronaviruses may drive these systems into a hyperactive state and cause the pathology we see in infected patients," Shapira says.

Human Studies Support Role of Viral Mimics in COVID

Over the course of the pandemic, it has become clear that many COVID patients have coagulation problems and some are now treated with anti-coagulants and drugs that limit complement activation.

In a separate paper published in Nature Medicine, the Columbia researchers found evidence that functional and genetic dysregulation in immune complement and coagulation proteins are associated with severe COVID-19 disease. They found that people with macular degeneration (which is associated with enhanced complement activation) were more likely to die from COVID-19, that complement and coagulation genes are more active in COVID-19 patients, and that people with certain mutations in complement and coagulation genes are more likely to be hospitalized for COVID-19.

Since that paper first appeared this spring in a preprint, other researchers have also found links between complement and COVID severity and several clinical trials of complement inhibitors have been initiated.

Shapira says the investigation of viral protein functions and mimicry suggests that learning about underlying virus biology could be one way to gain insights into how viruses cause disease and who may be at greatest risk.

"Viruses have already figured out how to exploit their hosts," Shapira says. "By studying viruses we can not only reveal fundamental principles in biology but also how they perturb cellular homeostasis and cause pathology. The hope is that one day we may be able to use this knowledge to fight back.

"Beyond COVID-19, the information we're gathering about how individual viral proteins work--across all viruses on Earth--may one day be leveraged as building blocks in medical and agricultural interventions."

WASHINGTON--Over 80 percent of 200 COVID-19 patients in a hospital in Spain have vitamin D deficiency, according to a new study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism.

Vitamin D is a hormone the kidneys produce that controls blood calcium concentration and impacts the immune system. Vitamin D deficiency has been linked to a variety of health concerns, although research is still underway into why the hormone impacts other systems of the body. Many studies point to the beneficial effect of vitamin D on the immune system, especially regarding protection against infections.

"One approach is to identify and treat vitamin D deficiency, especially in high-risk individuals such as the elderly, patients with comorbidities, and nursing home residents, who are the main target population for the COVID-19," said study co-author José L. Hernández, Ph.D., of the University of Cantabria in Santander, Spain. "Vitamin D treatment should be recommended in COVID-19 patients with low levels of vitamin D circulating in the blood since this approach might have beneficial effects in both the musculoskeletal and the immune system."

The researchers found 80 percent of 216 COVID-19 patients at the Hospital Universitario Marqués de Valdecilla had vitamin D deficiency, and men had lower vitamin D levels than women. COVID-19 patients with lower vitamin D levels also had raised serum levels of inflammatory markers such as ferritin and D-dimer.