Culture

Energy conservation lies at the core of every physical theory. Effective mathematical models however can feature energy gain and/or loss and thus break the energy conservation law by only capturing the physics of a subsystem. As a result, the Hamiltonian, the function that describes the system's energy, loses an important mathematical property: it is no longer Hermitian. Such non-Hermitian Hamiltonians have successfully described experimental setups for both classical problems - in e.g. some optical systems and electrical circuits - and quantum ones, in modelling the motion of electrons in crystalline solids. In a new paper in EPJ D, physicists Rebekka Koch from the University of Amsterdam in the Netherlands and Jan Carl Budich from Technische Universität Dresden, in Germany, describe how these functions provide new insights into behaviour at the edges of topological materials.

However, non-Hermitian Hamiltonians break with concepts that are known from energy-conserving systems such as the bulk-boundary correspondence (BBC) in these materials. This correspondence relates the topological properties of the bulk of the material to the physics of the edges. In the Hermitian case, the bulk of such a material can be described by neglecting the edges and just assuming the material to be infinite or periodic, since boundary effects do not affect the physics of the inside.

Surprisingly, this holds no longer true if the energy is not conserved: the properties of the boundary suddenly have a huge influence on the bulk system and subsequently have to be taken into account. It leads to a drastically altered BBC (bulk-boundary correspondence) for non-Hermitian systems. In particular, Koch and Budich studied different strengths of the coupling between boundaries and their effect on the bulk system. Knowing that in realistic quantum mechanical systems there is always an interaction between the edges - admittedly an extremely small one - they explored the extent to which decoupled edges are generally observable. Koch and Budich found that the spectrum of the topological material is stable under physically motivated perturbations such as the suppressed interactions between the boundaries.

Patients with Alzheimer's disease (AD) are often prescribed drugs for other conditions -- including diabetes or high blood pressure -- at the same doses as those without dementia. That practice might need to be reexamined in the wake of new mouse studies reported in ACS' Molecular Pharmaceutics. The findings suggest that AD could alter absorption of medications from the digestive tract, so dosages might need to be adjusted for these patients.

Because AD is primarily considered a disease of the nervous system, scientists have mostly focused on its impact on drug uptake across the blood-brain barrier (BBB). Their research revealed that the quantity and function of proteins that transport drugs through the BBB are altered in people with AD. Less attention has been given to other biological barriers, such as the intestine's lining, through which oral drugs pass into the bloodstream. The few small studies published on this subject, however, suggest that this absorption process may be disrupted in AD. Joseph A. Nicolazzo and colleagues wanted to know if these changes could occur with drugs commonly prescribed to AD patients.

Using mice that serve as a model for AD, the team measured absorption of compounds that move from the small intestine to the bloodstream through three different mechanisms. For example, blood plasma levels of diazepam, which diffuses passively through intestinal cells to reach the bloodstream, were similar in AD mice compared with control mice. But AD mice had less valsartan and digoxin in their plasma than controls. Passage of these drugs through intestinal cells is controlled by transporters that could be disrupted by AD, according to the team's prior research. These drugs may also pass through gaps between intestinal cells, and tissue samples indicated that these gaps might be more restrictive in AD mice. If these findings translate to people with AD, the researchers recommend revisiting dosing regimens for certain drugs to ensure their plasma concentrations remain in the appropriate range.

(Boston)--Women Veterans with more symptoms of post-traumatic stress disorder
(PTSD) or moral injury (guilt, shame or demoralization in response to participating in or witnessing events that violate one's sense of right and wrong), are at greater risk for negative pregnancy outcomes and postpartum depression in the three years following discharge from military service.

The number of women in the military and associated veteran population continues to
grow with the largest increases observed among women of child-bearing age.

More than 9,500 Veterans were enrolled in a study approximately three months following their discharge from the service. Every six months they completed surveys which included questions about current pregnancies and outcomes. A total of 318 women Veterans experienced a pregnancy in the three years following separation from military service.

The researchers found one in two women veterans (50 percent) who became pregnant during the study period experienced a negative pregnancy outcome. In addition, the proportion of women who reported experiencing other adverse outcomes were as follows:

Pregnancy Outcome Percentage

Postpartum depression or anxiety 30%

Miscarriage 25%

Obstetrical medical condition (such as preeclampsia or gestational diabetes) 22%

Emergency C-section 9%

Baby to NICU 8%

Preterm birth 6%

Stillbirth 2%

Ectopic or tubal pregnancy 2%

According to the researchers, the finding that PTSD and moral injury increase risk for these outcomes suggests that screening for these conditions is important. "Although depression screening has become more common in obstetric settings due to recommendations made by the U.S. Preventative Service Task Force, it is unlikely that screening for PTSD and moral injury are universally being conducted in these settings," explained leas author Yael I. Nillni, PhD, Clinical Research Psychologist in the National Center for PTSD, Women's Health Sciences Division at VA Boston Healthcare System and assistant professor of psychiatry at Boston University School of Medicine.

While screening for PTSD is common in VA medical centers, screening for PTSD in OB/GYN clinics in the community is not a widespread or common practice. "Given that many women veterans currently receive obstetric care outside of the VA, increased awareness of the impact of PTSD and moral injury on perinatal outcomes is imperative to improve screening during this sensitive time and connect at-risk veterans to services."

Gluten is enemy No. 1 for those with celiac disease, and it's hard to avoid. Episodes of this chronic autoimmune illness can be triggered by ingesting gluten, a key protein in wheat and some other grains. Researchers have been exploring how gut bacteria, especially Bifidobacteria, could be used as a treatment. Now, scientists publishing the results of laboratory experiments in ACS' Journal of Agricultural and Food Chemistry report how specific types of Bifidobacteria work.

Humans have many types of bacteria living in their digestive systems, but those with celiac disease have altered levels of "beneficial" and "harmful" gut bacteria. And even if they stick to a strict gluten-free diet, celiac disease patients typically cannot reestablish an ideal gut microbiome on their own. In particular, the levels of bacteria in the Bifidobacteria family are lower in those with the condition than in healthy individuals. These bacteria can chop up gluten proteins into smaller fragments that are not as triggering or damaging in patients, which has led researchers to try using the microbes as a probiotic to treat gastrointestinal diseases. So Edson Rodrigues-Filho, Natália E. C. de Almeida and colleagues set out to see exactly how various Bifidobacteria strains break down gluten peptides and what effect these smaller gluten-derived peptides would have on the immune response.

The researchers extracted gluten proteins from wheat flour and cultivated four strains of the Bifidobacteria family, both separately and in one large group. In an artificial intestinal environment, B. longum chopped up gluten proteins into the most fragments, compared to the other strains and the mixture of all four strains. From there, the team analyzed the cytotoxic and inflammatory responses to the various peptides, and found that those from the B. longum strain caused the least harm to intestinal cells in petri dishes. These results mark the first identification of specific gluten-derived peptides generated directly from intact gluten proteins by Bifidobacteria activity and the immunological responses to them by human cells, paving the way for new treatments and better patient outcomes, say the researchers. 

In "Aging and Public Health," a new special issue of the journal Innovation in Aging from The Gerontological Society of America, researchers look at public health interventions that work to foster healthy aging.

The issue's eight papers focus on how best to lengthen the period of good health, a sustained sense of well-being, and extended periods of social engagement and productivity as our society ages, while emphasizing elements in the realm of public health.

"Public health faces the challenge of designing, assessing, translating, and implementing programs that push interventions out to aging subpopulations that span a broad continuum of health and vulnerability," wrote Deputy Editor-in-Chief Steven M. Albert, PhD, FGSA, and Guest Associate Editor Vicki A. Freedman, PhD, in an opening editorial.

Three papers focus on making communities and service systems more age-friendly; three additional papers emphasize population surveillance of vulnerable subgroups of the aging population; and a pair of papers focus on programmatic innovations to address specific needs common among older adults.

Rather than focusing solely on how aging unfolds for individuals, articles in this issue emphasize the critical role of systems -- either through population health surveillance or through implementation of programs that utilize infrastructures on the ground, such as health departments, aging services providers, the Centers for Disease Control and Prevention (CDC), the Administration for Community Living/Administration on Aging, state units on aging, county human services, health systems, and national advocacy organizations.

"Papers in the special issue met the charge of applying a public health perspective to aging subpopulations that span the continuum of health and vulnerability," Albert and Freedman stated. "Not all components of public health could be addressed, and undoubtedly many other kinds of aging could profitably be pulled into the conversation. Still, this collection brings to bear the tools of public health, and this approach forces us to think about aging more broadly than we ordinarily do."

Cutting down forests means we're also cutting down woodland caribou, says a pioneering study by University of Guelph ecologists showing that logging in Ontario's extensive boreal stands threatens populations of the elusive but iconic herbivore.

In what integrative biology professor John Fryxell calls the first comprehensive study looking at the status of endangered woodland caribou across Ontario, the team found habitat and food web changes caused by forestry are encouraging more wolf packs to prey on caribou. Labelling the study a "clarion call" for conservation measures, he said the new paper shows how human activity, particularly logging, is upsetting food webs and habitat involving caribou, wolves and moose.

"It's death by a million cuts," said Fryxell. "Woodland caribou are an iconic species in Indigenous culture, integral to our historical development and a cornerstone in the functioning of boreal food webs. I think of the caribou as a canary in the coal mine for the long-term sustainability and quality of the boreal forest to protect other wildlife."

Published recently in the Journal of Wildlife Management, the study entailed attaching video collars to 30 caribou to monitor their foraging. The researchers also outfitted about 120 caribou and 50 wolves with regular GPS-tracking radio collars to monitor the animals' movements, including signs that wolves likely had killed a caribou.

Ontario's woodland caribou number several thousand animals. An officially endangered species, woodland caribou live below the tree line across most of Canada except the Atlantic provinces.

Logging has moved northward in Ontario over recent decades. As cut forests regrow, their mix of new trees and shrubs attracts moose. Higher moose populations in turn attract wolves, placing caribou at risk of being hunted as well.

Those caribou could move farther north, said Fryxell, but perhaps not soon enough to sustain their numbers.

Over six years, the team studied two sites in northern Ontario spanning about 23,000 square kilometres in all.

One site in Nakina, located about 160 kilometres north of Lake Superior, has been logged extensively since 1970. Regenerating forests contain more deciduous trees such as poplar and willow as well as thicker undergrowth.

The Pickle Lake site, dominated by stands of jack pine, is located about a seven-hour drive from Thunder Bay, beyond the northern limit for forestry. That made for a perfect natural experiment for the researchers to compare conditions in both locations.

To see what caribou might be eating, they sampled kinds of plants growing in each site and analyzed the footage collected from the video collars, or "critter cams." Caribou eat mostly lichen on the ground and growing on trees.

The researchers also analyzed the information collected from the GPS-tracking radio collars on wolves. Multiple pings from a single spot over an extended period "usually means they're eating something," said Fryxell.

Team members then visited those sites to verify what prey had been eaten.

The researchers entered their information into computer models that estimate whether a caribou population will produce enough young to sustain itself or not. They found that caribou in the disturbed site were not self-sustaining, unlike healthier populations at Pickle Lake

Fryxell said the results likely would apply farther north in Ontario and in other parts of Canada where woodland caribou are endangered by resource extraction.

He said forestry companies need to consider the long-term effects of their operations on plants and animals. Companies should practice rotation cutting to prevent clear-cutting and allow forests to regenerate, said Fryxell.

More immediately, resource managers might need to consider culling wolves or hindering their movements by turning old logging roads back into forest.

He said there's no evidence that either wolves or moose are threatened.

With plans for further development of Northern Ontario communities, Fryxell hopes to see governments, conservationists, Indigenous groups, industry and others work together to address threats to woodland caribou. "We have an opportunity to learn from what was done in the past to manage better in the future."

Regular exercise may reduce the risk of acute respiratory distress syndrome, a major cause of death in patients with the COVID-19 virus, a top exercise researcher reports. He is urging people to exercise based on his findings, which also suggest a potential treatment approach.

A review by Zhen Yan, PhD, of the University of Virginia School of Medicine, showed that medical research findings "strongly support" the possibility that exercise can prevent or at least reduce the severity of ARDS, which affects between 3% and 17% of all patients with COVID-19. Based on available information, the federal Centers for Disease Control and Prevention estimates 20% to 42% of patients hospitalized for COVID-19 will develop ARDS. The range for patients admitted to intensive care is estimated at 67% to 85%.

Research conducted prior to the pandemic suggested that approximately 45 percent of patients who develop severe ARDS will die.

"All you hear now is either social distancing or ventilator, as if all we can do is either avoiding exposure or relying on a ventilator to survive if we get infected," Yan said. "The flip side of the story is that approximately 80% of confirmed COVID-19 patients have mild symptoms with no need of respiratory support. The question is why. Our findings about an endogenous antioxidant enzyme provide important clues and have intrigued us to develop a novel therapeutic for ARDS caused by COVID-19."

Powerful Antioxidant

Yan, the director of the Center for Skeletal Muscle Research at UVA's Robert M. Berne Cardiovascular Research Center, compiled an in-depth review of existing medical research, including his own, looking at an antioxidant known as "extracellular superoxide dismutase" (EcSOD). This potent antioxidant hunts down harmful free radicals, protecting our tissues and helping to prevent disease. Our muscles naturally make EcSOD, secreting it into the circulation to allow binding to other vital organs, but its production is enhanced by cardiovascular exercise.

A decrease in the antioxidant is seen in several diseases, including acute lung disease, ischemic heart disease and kidney failure, Yan's review shows. Lab research in mice suggests that blocking its production worsens heart problems, while increasing it has a beneficial effect. A decrease in EcSOD is also associated with chronic conditions such as osteoarthritis.

Research suggests that even a single session of exercise increases production of the antioxidant, prompting Yan to urge people to find ways to exercise even while maintaining social distancing. "We cannot live in isolation forever," he said. "Regular exercise has far more health benefits than we know. The protection against this severe respiratory disease condition is just one of the many examples."

Potential Treatments

Yan's review also suggests EcSOD as a potential treatment for ARDS and many other health conditions. Gene therapy, for example, might one day be used to increase production of the antioxidant so that its protective presence in the lungs is enhanced in patients battling COVID-19.

Research has also shown that lab rats with chronic kidney disease had less kidney damage when treated with human EcSOD. The antioxidant is already being proposed as a potential therapeutic for diabetic retinopathy, a complication of diabetes that can lead to blindness.

Further, EcSOD also may prove beneficial against multi-organ dysfunction syndrome, in which multiple organs begin to fail. Efforts to treat the condition with general antioxidants have been unsuccessful, but Yan suggests that understanding EcSOD's workings may let doctors use it in a more targeted - and hopefully more effective - fashion.

"We often say that exercise is medicine. EcSOD set a perfect example that we can learn from the biological process of exercise to advance medicine," Yan said. "While we strive to learn more about the mysteries about the superb benefits of regular exercise, we do not have to wait until we know everything."

When adult brain cells are injured, they revert to an embryonic state, according to new findings published in the April 15, 2020 issue of Nature by researchers at University of California San Diego School of Medicine, with colleagues elsewhere. The scientists report that in their newly adopted immature state, the cells become capable of re-growing new connections that, under the right conditions, can help to restore lost function.

Repairing damage to the brain and spinal cord may be medical science's most daunting challenge. Until relatively recently, it seemed an impossible task. The new study lays out a "transcriptional roadmap of regeneration in the adult brain."

"Using the incredible tools of modern neuroscience, molecular genetics, virology and computational power, we were able for the first time to identify how the entire set of genes in an adult brain cell resets itself in order to regenerate. This gives us fundamental insight into how, at a transcriptional level, regeneration happens," said senior author Mark Tuszynski, MD, PhD, professor of neuroscience and director of the Translational Neuroscience Institute at UC San Diego School of Medicine.

Using a mouse model, Tuszynski and colleagues discovered that after injury, mature neurons in adult brains revert back to an embryonic state. "Who would have thought," said Tuszynski. "Only 20 years ago, we were thinking of the adult brain as static, terminally differentiated, fully established and immutable."

But work by Fred "Rusty" Gage, PhD, president and a professor at the Salk Institute for Biological Studies and an adjunct professor at UC San Diego, and others found that new brain cells are continually produced in the hippocampus and subventricular zone, replenishing these brain regions throughout life.

"Our work further radicalizes this concept," Tuszynski said. "The brain's ability to repair or replace itself is not limited to just two areas. Instead, when an adult brain cell of the cortex is injured, it reverts (at a transcriptional level) to an embryonic cortical neuron. And in this reverted, far less mature state, it can now regrow axons if it is provided an environment to grow into. In my view, this is the most notable feature of the study and is downright shocking."

To provide an "encouraging environment for regrowth," Tuszynski and colleagues investigated how damaged neurons respond after a spinal cord injury. In recent years, researchers have significantly advanced the possibility of using grafted neural stem cells to spur spinal cord injury repairs and restore lost function, essentially by inducing neurons to extend axons through and across an injury site, reconnecting severed nerves.

Last year, for example, a multi-disciplinary team led by Kobi Koffler, PhD, assistant professor of neuroscience, Tuszynski, and Shaochen Chen, PhD, professor of nanoengineering and a faculty member in the Institute of Engineering in Medicine at UC San Diego, described using 3D printed implants to promote nerve cell growth in spinal cord injuries in rats, restoring connections and lost functions.

The latest study produced a second surprise: In promoting neuronal growth and repair, one of the essential genetic pathways involves the gene Huntingtin (HTT), which, when mutated, causes Huntington's disease, a devastating disorder characterized by the progressive breakdown of nerve cells in the brain.

Tuszynski's team found that the "regenerative transcriptome" -- the collection of messenger RNA molecules used by corticospinal neurons -- is sustained by the HTT gene. In mice genetically engineered to lack the HTT gene, spinal cord injuries showed significantly less neuronal sprouting and regeneration.

"While a lot of work has been done on trying to understand why Huntingtin mutations cause disease, far less is understood about the normal role of Huntingtin," Tuszynski said. "Our work shows that Huntingtin is essential for promoting repair of brain neurons. Thus, mutations in this gene would be predicted to result in a loss of the adult neuron to repair itself. This, in turn, might result in the slow neuronal degeneration that results in Huntington's disease."

LAWRENCE -- You might own something made from mahogany like furniture, paneling or a musical instrument.

Mahogany is a commercially important wood, valued for its hardness and beauty. The United States is the world's top importer of the tropical timber from leading producers like Peru and Brazil. Unfortunately, mahogany is harvested illegally a lot of the time.

For science, mahogany is important, too -- the fossil presence of the mahogany family is a telltale of where tropical forests once stood. Until recently, paleobotanists had only found evidence the mahogany family extended back to the Paleocene (about 60 million years ago).

Now, a new paper written by University of Kansas researcher Brian Atkinson in the American Journal of Botany shows the mahogany family goes back millions of years more, to the last hurrah of the dinosaurs, the Cretaceous.

"For understanding when many of the different branches of the tree of life evolved, we're primarily dependent on the fossil record," said Atkinson, an assistant professor of ecology & evolutionary biology and curator in the Biodiversity Institute's Division of Paleobotany. "In this case, Meliaceae, the mahogany family, is an ecologically and economically important group of trees. A lot of researchers have used this group as a study system to better understand the evolution of tropical rainforests. This work is the first definitive evidence that the tropically important trees were around during the Cretaceous period, when we first start to see the modernization of ecosystems and modern groups of plants."

Atkinson's new work pushes back the fossil record for Meliaceae by 15 to 20 million years, the Campanian stage of the Late Cretaceous, from between 72-79 million years ago. The well-preserved mahogany specimen Atkinson analyzed was discovered just off Vancouver Island in Canada.

"The rock that contained the specimen was collected by a local fossil collector, Graham Beard, who is the director of the Qualicum Beach Museum of Natural History," Atkinson said. "He collected it years ago, but I was actually interested in the rock that has this fossil in it for something else. And as I kept preparing this rock, more for the other fossils were in there, this thing showed up by surprise. So, it was kind of found by accident."

To pinpoint the fossil's identity, Atkinson carefully studied the structure of the fossilized fruit and also analyzed phylogenetic information to figure out its relationship to other species in the mahogany family.

"I combined the molecular data from living representatives of the mahogany family with the morphology of the fossil, as well as the morphology of living species," he said. "And then I subjugated that combined dataset to phylogenetic analyses, which allows us to reconstruct evolutionary relationships. Based on this analysis, we found the fossil is closely related to this genus called Melia, which is living today."

The KU researcher gave the oldest-known mahogany fossil the scientific name Manchestercarpa vancouverensis -- the species name signifies where the specimen was discovered, and the genus is named after an esteemed colleague in the field.

"I named it after a prolific paleobotanist who's really improved our understanding of the evolution of flowering plants through the fossil record," Atkinson said. "So, I named it in honor of Steve Manchester, who's at the University of Florida Museum of Natural History."

While it's noteworthy that Atkinson has pushed back the origin story of mahogany, he stressed it also helps improve our understanding of the rate of early flowering plant evolution and, in turn, our grasp of larger modern ecosystems.

"They're our most diverse group of plants on Earth, and so there's a whole lot to explore," he said. "And there are some cool things you can do methodologically that you might not be able to do with other groups of plants. I can really ask some exciting paleontological and general evolutionary questions with this group."

People handle monarch butterflies. A lot. Every year thousands of monarch butterflies are caught, tagged and released during their fall migration by citizen scientists helping to track their movements. And thousands of caterpillars are reared by hand or used in classroom demonstrations and outreach events.

These activities can provide valuable scientific data and educational benefits for the people participating in them. But how do the monarchs themselves feel about being handled by humans?

The answer, according to a new study from University of Georgia ecologist Andy Davis, depends on their life stage: Being handled is stressful to them but only in their early life.

"Most people don't realize that insects get stressed in much the same way as vertebrates do," said Davis, an assistant research scientist in the Odum School of Ecology. "People handle monarchs for all of these activities, but if you imagine yourself in their place, what would it be like for us if a 50-foot-tall robot picked us up and passed us around? From the monarch's perspective, maybe for them this is akin to being attacked by a predator."

Stress reactions in insects include elevated heart rates, which are part of the fight-or-flight response triggered by predators--or perceived predators--so Davis designed a series of experiments to find out whether the heart rates of monarchs rose after handling.

Because they are subject to human contact at all life stages--larval, pupal and adult--he measured the heart rates of caterpillars, chrysalises and butterflies before and after short periods of gentle handling.

Davis first looked at caterpillars under a microscope, and counted how fast their hearts beat before handling. Then he gently passed the caterpillar from hand to hand for three minutes and observed its heart rate again.

The procedure was similar for adult butterflies, which Davis netted during fall migration. Within 30 seconds of catching each one, he held it carefully under a microscope to observe its heart beats. He then simulated the procedure for tagging them and measured their heart rates again.

Measuring the heart rates of monarch pupae required a different approach. Because they are encased in a chrysalis, their heart beats can't be observed under a microscope. Davis instead used an electronic device that could remotely detect heart movement inside the chrysalis and provide a readout to his computer.

Making the process even more complicated was the unusual cardiac function of monarch pupae.

"At the pupal stage, their hearts beat in a weird way," Davis said. "The heart will beat for about 15 minutes and then stop for up to two hours; it flatlines."

The monarch heart also reacts very quickly to disturbance, so he gently prodded or jostled the chrysalises for 20 seconds and recorded their heart rates for the next minute using the electronic device.

He found that handling did indeed have an effect on heart rates at the two early stages of life. Caterpillars experienced an approximately 20% increase above their baseline heart rate, and pupal heart rates shot from zero to 88 beats per minute--which is almost three times higher than the typical active beating rate for pupae as reported in earlier research.

The heart rates of adult butterflies, however, showed no significant change after handling. This could mean either that the experiment didn't capture the adult butterflies' stress reaction or that gentle handling doesn't cause them stress.

Davis suspects it's the latter.

"It kind of makes sense that adult monarchs would be fairly stress-tolerant," he said. "The migration itself is fraught with dangers and perils along the way, and for a monarch to be able to accomplish that, it has to be able to deal with a wide variety of natural stressors."

Davis said that just because larvae and pupae seem prone to stress reactions from handling, the study shouldn't be interpreted to mean that people shouldn't work with monarchs.

"These results don't mean people should stop important activities like research and outreach," he said. "But the results should at least make us more cognizant about how the monarch is feeling about being handled. In other words, we shouldn't kid ourselves by thinking the monarchs are OK with it."

DALLAS - April 15, 2020 - Researchers at UT Southwestern Medical Center have uncovered the detailed shape of a key protein involved in muscle contraction. The report, published today in Neuron, may lead to improved understanding of muscle-weakening genetic conditions called congenital myasthenic syndromes (CMS).

The protein sits on the surface of nerve cells that connect to muscles and is integral to triggering the muscle cell to contract just milliseconds after instructions are sent through the spinal cord. Called a nicotinic receptor, it has been a challenge to study because it sits in the cell's membrane.

"The nicotinic receptor at the neuromuscular junction has been a target of interest for over a century. It was the first ion channel to be purified, the first to have its genes cloned, and the first to be imaged by an electron microscope," says Ryan Hibbs, Ph.D., associate professor of Neuroscience and Biophysics at UTSW and a corresponding author of the study.

Many groups had tried to determine the receptor's structure using an earlier technology called X-ray crystallography as well as first generation cryogenic electron microscopes (cryo-EM) but they were only able to obtain low-resolution images, he adds.

Normally the nicotinic receptor is activated by a molecule called acetylcholine. However, the nicotinic receptor is also the target of various venoms that cause muscle paralysis.

So the team used this to their advantage to isolate enough of the receptor protein to study its shape and structure. They mixed the toxin from snake venom with fish tissue known to contain high amounts of the receptor protein.

The team then flash froze the receptor bound to the toxin and used the rapidly evolving technique of cryo-electron microscopy to uncover the shape of the structure. Before recent developments in cryo-EM, the only method by which to solve protein structures like the nicotinic receptor was X-ray crystallography, which involved slowly growing crystals of proteins. But proteins that sit in membranes usually do not crystallize well.

"This never could have been done using X-ray crystallography - hundreds of researchers had attempted it. The new microscopes allowed us to get to a very high resolution near the atomic level. At that resolution, we can precisely make out the positions of most of more than 2,000 amino acids that make up the receptor protein," Hibbs says. "The results were stunning. They revealed, at a very fine level of detail, the 3D architecture of the receptor, with two toxin molecules bound to it exactly where we know the much smaller acetylcholine binds."

The results showed how the toxin blocks acetylcholine by competing for the same binding site, paralyzing the receptor in the closed configuration and preventing the flow of electrochemical messages. The structure also reveals why the toxin binds so tightly and selectively to the receptor and how the venom paralyzes prey, including humans, who are unfortunate enough to get bitten by the snake.

"We learned a tremendous amount from the new 3D structure beyond how the toxin works to poison the receptor," Hibbs says. Lead author Md. Mahfuzur Rahman, Ph.D., a postdoctoral researcher in the Hibbs lab, adds that the nicotinic acetylcholine neuromuscular receptor is a therapeutic target for several genetic diseases that cause muscle weakness, which the team also investigated.

"Here we mapped the mutations related to CMS to three principal regions on the receptor structure. This new structural information sheds light on how mutations in those areas result in muscle-weakening syndromes," Rahman says.

Two months after creating a structural 3D roadmap of the novel coronavirus and sharing it with the scientific community worldwide, Worcester Polytechnic Institute (WPI) bioinformatics researcher Dmitry Korkin has published a paper on the topic in Viruses, a leading virology journal.

In the peer-reviewed paper, Korkin, associate professor of computer science at WPI and director of the university’s bioinformatics and computational biology program, describes how he and his research team of graduate students used bioinformatics and molecular modeling to reconstruct the 3D structure of major viral proteins and their interactions with human proteins.

Specifically, the team found three Severe Acute Respiratory Syndrome (SARS) isolates—or specimens—that were similar to COVID-19, a new disease caused by a novel coronavirus that has not been seen before in humans. SARS, a virus identified in 2003, also caused worldwide infection and a significant number of deaths.

Korkin and his team reached three preliminary conclusions that could play a part in modeling the virus and aiding scientists with future drug discovery. First they determined that changes in the proteins constituting the novel coronavirus were not distributed evenly, but often formed clusters on the protein surfaces when compared to human SARS virus and the other related animal viruses.

Second, his group showed that the region of “spike protein,” a protein on the surface of the new virus that would be targeted by human antibodies, is very different from the same region in SARS, suggesting that the existing SARS vaccine might not be efficient and a new vaccine is required.

At the same time, a third conclusion the team made is that the regions targeted by the previously developed SARS antiviral drug candidates were remarkably intact, suggesting that repurposing of those drugs is possible.

“The goal of this computational work is twofold,” Korkin wrote in Viruses, an open access journal published monthly online. He said he wanted to “…make the structural road map and the related findings fully available to the research community” and “…help experimental scientists in their deciphering of the molecular mechanisms implicated in infection by the new coronavirus as well as in vaccine development and antiviral drug discovery.”

In the United States, the Centers for Disease Control and Prevention reported nearly 580,000 cases and more than 22,000 deaths of COVID-19 by mid-April. According to the World Health Organization, the number of cases has reached into the millions, resulting in more than 100,000 deaths globally. 

In February, Korkin and his research team created and unveiled a structural 3D roadmap of the new Coronavirus. At that time, Korkin shared the roadmap with researchers worldwide in an effort to spur greater research about the disease.

To get the findings out quickly to the research community, Korkin’s complete 3D structural roadmap dataset and a manuscript preprint was posted on Feb. 14 on bioRxiv, a free online archive and distribution service for unpublished preprints in the life sciences operated by Cold Spring Harbor Laboratory, a not-for-profit research and educational institution.

Korkin is pleased with the publication in Viruses, noting that it validates his earlier work.

“The publication in Viruses strengthens our hopes that the work our team has developed over the past three months will add significant value to the research community in the joint effort to fight the disease,” said Korkin. “We are very pleased that our work has been formally reviewed and is available to anyone as an open-access publication.”

"Probiotic" is a broad term that refers to a range of different microorganisms that confer health benefits. Just as medications are identified by product names that connect them to the conditions they treat, probiotics are referred to by specific names that link them to scientifically-demonstrated health effects. A complete probiotic name includes the Latin name for genus and species, in addition to the strain: for example, Lactobacillus rhamnosus GG.

A global group of scientists, led by Prof. Giovanna Felis of Italy, Prof. Michael Ganzle of Canada, and Prof. Sarah Lebeer of Belgium, has recently published a paper announcing name changes for some of the bacteria that were historically grouped under the category of Lactobacillus. Members of the Lactobacillus genus are among the most popular bacteria found in consumer probiotic products and fermented foods.

The impetus for the name changes comes from new scientific tools developed over the past few decades, which enable scientists to look at bacterial genes. Now that scientists are able to sequence the genes of bacteria, they have information about which ones are closely genetically related and they are changing the bacterial names to better reflect these relationships. Thus, the wide variety of bacteria that were previously grouped under Lactobacillus have been separated into 25 different genera.

According to the naming conventions for all living things, the first species ever described as a Lactobacillus gets to retain its genus name - so the yogurt-making bacterial species Lactobacillus delbruecki will keep its name, along with the bacteria that are closely related to it.

The new paper, which includes International Scientific Association for Probiotics and Prebiotics board member Dr. Sarah Lebeer as co-author, was published in the International Journal of Systematic and Evolutionary Biology. Lebeer says, "This task had been on the agenda of scientists for a while. We are pleased that we managed to unite different international teams working on comparative genomics of Lactobacillus with taxonomy experts, collaborating for the best interest of the whole field."

Lebeer adds, "I admit it's a bit painful to see the names of my favorite bacteria change (including Lacticaseibacillus rhamnosus GG for LGG). Yet I look forward to the new insights provided by this comprehensive analysis of taxonomy, evolutionary history, physiology, and ecology of lactobacilli. The most closely related bacteria sharing most properties now have the same genus name, while lactobacilli that are more distantly related can be more clearly discriminated from each other."

The paper authors have created a website where the previous names and the new names of the bacteria can be searched.

The bacteria in consumer products will remain the same after these name changes are implemented, but their product labels will be updated. Because only the genus names are affected (and many new genus names were deliberately chosen to begin with the letter 'L'), most products will remain easy to recognize.

The paper proposes splitting the existing genus Lactobacillus into Lactobacillus and Paralactobacillus, as well as 23 new genera with the following names: Holzapfelia, Amylolactobacillus, Bombilactobacillus, Companilactobacillus, Lapidilactobacillus, Agrilactobacillus, Schleiferilactobacillus, Loigolactobacilus, Lacticaseibacillus, Latilactobacillus, Dellaglioa, Liquorilactobacillus, Ligilactobacillus, Lactiplantibacillus, Furfurilactobacillus, Paucilactobacillus, Limosilactobacillus, Fructilactobacillus, Acetilactobacillus, Apilactobacillus, Levilactobacillus, Secundilactobacillus, and Lentilactobacillus.

ISAPP has created an infographic explaining these name changes for consumers.

Irvine, Calif., April 15, 2020 - On Tuesday, California Gov. Gavin Newsom suggested that reopening the state's economy will require six steps, the first of which involves "tracing and tracking individuals" in order to identify those who need to remain in isolation.

Researchers at the University of California, Irvine have developed a tool that could be instrumental in this effort. TrackCOVID is a free, open-source smartphone application that permits contact tracing for potential coronavirus infections while preserving privacy.

The team's project is detailed in a paper published recently in JMIR mHealth and uHealth.

"Contact tracing is the process of tracking down and isolating people who may have been exposed to an infectious disease after someone has tested positive," said lead author Tyler Yasaka, a software engineer and junior specialist in otolaryngology at the UCI School of Medicine. "This process has traditionally been slow and inefficient, and current technology-based solutions have privacy concerns because they require continuous tracking of everyone's location."

TrackCOVID works in a different way, he said, by creating an anonymous graph of interactions. Every time a person gathers with others or goes to a public place, he or she can use the app to log contacts by either hosting or joining a checkpoint, which allows possible paths of virus transmission to be discovered. The first person to register as a checkpoint host is given a Quick Response code; others subsequently join the checkpoint by scanning this QR code.

As people congregate with others over time, their interactions are linked to each other anonymously. Anyone who tests positive for COVID-19 can report it through the app without revealing his or her identity. Using the graph of interactions, the app will notify users who may be at elevated risk of exposure.

"We built a simplified simulation model that showed the app is more effective - that it flattens the curve of infections - when more people use it," said co-author Dr. Ronald Sahyouni, a biomedical engineer in UCI's joint M.D./Ph.D. Medical Scientist Training Program and an incoming neurosurgery resident at UC San Diego.

How could this be encouraged? Co-author Brandon Lehrich, who earned a B.S. in biomedical engineering at UCI in 2018, suggested that endorsement by local, state and national government entities would be beneficial - as would enlisting the help of grocery stores and other "essential" gathering places.

The establishments could post signs displaying their QR code, which visitors could scan with their smartphones. TrackCOVID would open automatically in their device browsers, and they'd be anonymously checked into that specific location.

"If the customer happens to be at an elevated risk level, they'll see an alert on their screen," Lehrich said. "If enough public places are doing this, then a lot of contact tracing will happen without any users making a conscious effort other than scanning a QR code when they go shopping. From there, I think people will start to see the value of the app and begin using it to create checkpoints for their private interactions as well."

Yasaka added, "We hope our app goes viral before too many more people come in contact with the more dangerous virus."

Ever since the outbreak of the SARS-CoV-2, scientists have been scrambling to identify the species of origin to understand how the new coronavirus first leapt from its animal hosts to humans, causing the current pandemic infecting more than a million people worldwide.

Scientists have been looking for an intermediate animal host between bats, which are known to harbor many coronaviruses, and the first introduction of SARS-CoV-2 into humans.

Many animals, beginning with snakes and most recently, pangolins, have all been put forth as the likely intermediate, but the viruses isolated from them are too divergent from SARS-CoV-2, suggesting a common ancestor too far back in time---living in the 1960s[1].

Now, University of Ottawa biology professor Xuhua Xia, tracing coronavirus signatures across different species, has proposed that stray dogs---specifically dog intestines--- may have been the origin of the current SARS-CoV-2 pandemic.

"Our observations have allowed the formation of a new hypothesis for the origin and initial transmission of SARS-CoV-2," said Xia. "The ancestor of SARS-CoV-2 and its nearest relative, a bat coronavirus, infected the intestine of canids, most likely resulting in a rapid evolution of the virus in canids and its jump into humans. This suggests the importance of monitoring SARS-like coronaviruses in feral dogs in the fight against SARS-CoV-2."

The findings appear in the advanced access online edition of the journal Molecular Biology and Evolution.

Xia has long-studied the molecular signatures of viruses in different hosts. When viruses invade a host, their genomes often bear the battle scars from fighting off and evading the host's immune system through changes and adaptations found within their genomes.

Humans and mammals have a key antiviral sentinel protein, called ZAP, which can stop a virus in its tracks by preventing its multiplication in the host and degrading its genome. The viral target is a pair of chemical letters, called CpG dinucleotides, within its RNA genome. CpG dinucleotides act as a signpost that a person's immune system uses to seek and destroy a virus. ZAP patrols human lungs, and is made in large amounts in the bone marrow and lymph nodes, where the immune system first primes its attack.

But it's been shown that viruses can punch back. Single-stranded coronaviruses, like SARS-CoV, can avoid ZAP by reducing these CpG signposts, thus rendering ZAP powerless. A similar examination of HIV, another RNA virus, shows that it has also exploited this evolutionary trick to lose CpG in response to human antiviral defenses. One implication of this is that the remaining CpG dinucleotides on the viral genome are likely functionally important for the virus and could serve as target of modification to attenuate virulence in vaccine development.

"Think of a decreased amount of CpG in a viral pathogen as an increased threat to public health, while an increased amount of CpG decreases the threat of such viral pathogens," said Xia. "A virus with an increased amount of CpG would be better targeted by the host immune system, and result in reduced virulence, which would be akin to natural vaccines."

To perform the study, Xia examined all 1252 full-length betacoronavirus genomes deposited into GenBank to date. Xia found that SARS-CoV-2 and its most closely related known relative, a bat coronavirus (BatCoV RaTG13), have the lowest amount of CpG among its close coronavirus relatives.

"The most striking pattern is an isolated but dramatic downward shift in viral genomic CpG in the lineage leading to BatCoV RaTG13 which was reported to be sampled from a bat (Rhinolophus affinis) in Yunnan Province in 2013 but only sequenced by Wuhan Institute of Virology after the outbreak of SARS-CoV-2 infection in late 2019," said Xia. "This bat CoV genome is the closest phylogenetic relative of SARS-CoV-2, sharing 96% sequence similarity."

"In this context, it is unfortunate that BatCoV RaTG13 was not sequenced in 2013, otherwise the downshifting in CpG might have served as a warning due to two highly significant implications," said Xia. "First, the virus likely evolved in a tissue with high ZAP expression which favors viral genomes with a low CpG. Second and more importantly, survival of the virus indicates that it has successfully evaded ZAP-mediated antiviral defense. In other words, the virus has become stealthy and dangerous to humans."

Xia applied his CpG tool to reexamining the camel origin of MERS, and found
those viruses infecting camel digestive system also had lower genomic CpG than those infecting camel respiratory system.

When he examined the data in dogs, he found that only genomes from canine coronaviruses (CCoVs), which had caused a highly contagious intestinal disease worldwide in dogs, have genomic CpG values similar to those observed in SARS-CoV-2 and BatCoV RaTG13. Second, canids, like camels, also have coronaviruses infecting their digestive system with CpG lower than those infecting their respiratory system (canine respiratory coronavirus or CRCoV belonging to BetaCoV).

In addition, the known cellular receptor for SARS-CoV-2 entry into the cell is ACE2 (angiotensin I converting enzyme 2). ACE2 is made in the human digestive system, at the highest levels in the small intestine and duodenum, with relatively low expression in the lung. This suggests that mammalian digestive systems are likely to be a key target infected by coronaviruses.

"This is consistent with the interpretation that the low CpG in SARS-CoV-2 was acquired by the ancestor of SARS-CoV-2 evolving in mammalian digestive systems and interpretation is further corroborated by a recent report that a high proportion of COVID-19 patients also suffer from digestive discomfort," said Xia. "In fact, 48.5% presented with digestive symptoms as their chief complaint."

Humans are the only other host species Xia observed to produce coronavirus genomes with low genomic CpG values. In a comprehensive study of the first 12 COVID-19 patients in the U.S., one patient reported diarrhea as the initial symptom before developing fever and cough, and stool samples from 7 out of 10 patients tested positive for SARS-CoV-2, including 3 patients with diarrhea.

Canids are often observed to lick their anal and genital regions, not only during mating but also in other circumstances. Such behavior would facilitate viral transmission from the digestive system to the respiratory system and the interchange between a gastrointestinal pathogen and a respiratory tract and lung pathogen.

"In this context, it is significant that the bat coronavirus (BatCoV RaTG13), as documented in its genomic sequence in GenBank (MN996532), was isolated from a fecal swab. These observations are consistent with the hypothesis that SARS-CoV-2 has evolved in mammalian intestine or tissues associated with intestine."

Another finding of Xia's study involves viruses recently isolated from pangolins. Nine SARS-CoV-2-like genomes have recently been isolated and sequenced from pangolin and deposited in GISAID database (gisaid.org). "The one with the highest sequence coverage (GISAID ID: EPI_ISL_410721) has an ICpG value of 0.3929, close to the extreme low end of the CpG values observed among available SARS-CoV-2 genomes. Thus, SARS-CoV-2, BatCoV RaTG13 and those from pangolin may either have a common ancestor with a low CpG or have convergently evolved low CpG values."

Based on his results, Xia presents a scenario in which the coronavirus first spread from bats to stray dogs eating bat meat. Next, the presumably strong selection against CpG in the viral RNA genome in canid intestines resulted in rapid evolution of the virus leading to reduced genomic CpG. Finally, the reduced viral genomic CpG allowed the virus to evade human ZAP-mediated immune response and became a severe human pathogen.

"While the specific origins of SARS-CoV-2 are of vital interest in the current world health crisis, this study more broadly suggests that important evidence of viral evolution can be revealed by consideration of the interaction of host defenses with viral genomes, including selective pressure exerted by host tissues on viral genome composition," said Xia.