Culture

The hunt for an effective treatment for COVID-19 has led one team of researchers to find an improbable ally for their work: a llama named Winter. The team -- from The University of Texas at Austin, the National Institutes of Health and Ghent University in Belgium -- reports their findings about a potential avenue for a coronavirus treatment involving llamas on May 5 in the journal Cell. The paper is currently available online as a "pre-proof," meaning it is peer-reviewed but undergoing final formatting.

The researchers linked two copies of a special kind of antibody produced by llamas to create a new antibody that binds tightly to a key protein on the coronavirus that causes COVID-19. This protein, called the spike protein, allows the virus to break into host cells. Initial tests indicate that the antibody blocks viruses that display this spike protein from infecting cells in culture.

"This is one of the first antibodies known to neutralize SARS-CoV-2," said Jason McLellan, associate professor of molecular biosciences at UT Austin and co-senior author, referring to the virus that causes COVID-19.

The team is now preparing to conduct preclinical studies in animals such as hamsters or nonhuman primates, with the hopes of next testing in humans. The goal is to develop a treatment that would help people soon after infection with the virus.

"Vaccines have to be given a month or two before infection to provide protection," McLellan said. "With antibody therapies, you're directly giving somebody the protective antibodies and so, immediately after treatment, they should be protected. The antibodies could also be used to treat somebody who is already sick to lessen the severity of the disease."

This would be especially helpful for vulnerable groups such as elderly people, who mount a modest response to vaccines, which means that their protection may be incomplete. Health care workers and other people at increased risk of exposure to the virus can also benefit from immediate protection.

When llamas' immune systems detect foreign invaders such as bacteria and viruses, these animals (and other camelids such as alpacas) produce two types of antibodies: one that is similar to human antibodies and another that's only about a quarter of the size. These smaller ones, called single-domain antibodies or nanobodies, can be nebulized and used in an inhaler.

"That makes them potentially really interesting as a drug for a respiratory pathogen because you're delivering it right to the site of infection," said Daniel Wrapp, a graduate student in McLellan's lab and co-first author of the paper.

Meet Winter

Winter, the llama, is 4 years old and still living on a farm in the Belgian countryside along with approximately 130 other llamas and alpacas. Her part in the experiment happened in 2016 when she was about 9 months old and the researchers were studying two earlier coronaviruses: SARS-CoV-1 and MERS-CoV. In a process similar to humans getting shots to immunize them against a virus, she was injected with stabilized spike proteins from those viruses over the course of about six weeks.

Next, researchers collected a blood sample and isolated antibodies that bound to each version of the spike protein. One showed real promise in stopping a virus that displays spike proteins from SARS-CoV-1 from infecting cells in culture.

"That was exciting to me because I'd been working on this for years," Wrapp said. "But there wasn't a big need for a coronavirus treatment then. This was just basic research. Now, this can potentially have some translational implications, too."

The team engineered the new antibody that shows promise for treating the current SARS-CoV-2 by linking two copies of the llama antibody that worked against the earlier SARS virus. They demonstrated that the new antibody neutralizes viruses displaying spike proteins from SARS-CoV-2 in cell cultures. The scientists were able to complete this research and publish it in a top journal in a matter of weeks thanks to the years of work they'd already done on related coronaviruses.

McLellan also led the team that first mapped the spike protein of SARS-CoV-2, a critical step toward a vaccine. (Wrapp also co-authored that paper along with other authors on the current Cell paper, including UT Austin's Nianshuang Wang, and Kizzmekia S. Corbett and Barney Graham of the National Institute of Allergy and Infectious Diseases' Vaccine Research Center.) Besides Wrapp, the paper's other co-first author is Dorien De Vlieger, a postdoctoral scientist at Ghent University's Vlaams Institute for Biotechnology (VIB), and the other senior authors besides McLellan are Bert Schepens and Xavier Saelens, both at VIB.

This work was supported by the National Institute of Allergy and Infectious Diseases (U.S.), VIB, The Research Foundation-Flanders (Belgium), Flanders Innovation and Entrepreneurship (Belgium) and the Federal Ministry of Education and Research (Germany).

Backstory

The first antibodies the team identified in the initial SARS-CoV-1 and MERS-CoV tests included one called VHH-72, which bound tightly to spike proteins on SARS-CoV-1. In so doing, it prevented a pseudotyped virus -- a virus that can't make people sick and has been genetically engineered to display copies of the SARS-CoV-1 spike protein on its surface -- from infecting cells.

When SARS-CoV-2 emerged and triggered the COVID-19 pandemic, the team wondered whether the antibody they discovered for SARS-CoV-1 would also be effective against its viral cousin. They discovered that it did bind to SARS-CoV-2's spike protein too, albeit weakly. The engineering they did to make it bind more effectively involved linking two copies of VHH-72, which they then showed neutralizes a pseudotyped virus sporting spike proteins from SARS-CoV-2. This is the first known antibody that neutralizes both SARS-CoV-1 and SARS-CoV-2.

Four years ago, De Vlieger was developing antivirals against influenza A when Bert Schepens and Xavier Saelens asked whether she would be interested in helping to isolate antibodies against coronaviruses from llamas.

"I thought this would be a small side project," she said. "Now the scientific impact of this project became bigger than I could ever expect. It's amazing how unpredictable viruses can be."

ITHACA, N.Y. - Cornell scientists have developed a new technique for imaging a zebrafish's brain at all stages of its development, which could have implications for the study of human brain disorders, including autism.

Zebrafish are translucent when young, making them good models for live imaging, but they become opaque with age, which has prevented researchers from seeing into a live adult brain.

Now, an interdisciplinary team from Cornell Neurotech has developed a microscopy tool to use with adult zebrafish engineered with calcium sensors that light up to reveal when neurons are activated.

Since all vertebrate brains are fundamentally similar, the approach allows scientists to learn basic principles of brain structure and function that apply to all vertebrates, including humans.

"All vertebrate brains are, to a first approximation, the same, with nearly all brain regions [present] in nearly every vertebrate," said Joseph Fetcho, professor of neurobiology and behavior and director of Cornell Neurotech in the College of Arts and Sciences. "This is not surprising because they all, even the simplest ones, have to do the same things to survive and reproduce."

Fetcho is a co-senior author of the study, "Deep Three-Photon Imaging of the Brain in Intact Adult Zebrafish," which published April 27 in Nature Methods. The other senior author is Chris Xu, professor of applied engineering and physics in the College of Engineering and the Mong Family Foundation Director of Cornell Neurotech-Engineering.

When nerve cells activate, they flood with calcium. The fish used in Fetcho's studies are engineered with a protein that binds to the calcium in nerve cells. The protein also fluoresces when excited by laser light with a 480-nanometer wavelength, and the fluorescing cells can be imaged with a microscope.

The problem: When delivering that pulse of light, a single 480nm photon aimed through the top of the fish's head will excite other fluorescent proteins in the beam's path, blurring the image. The new technique works by delivering 1400nm wavelength photons to a focal point in the brain. This way, each individual photon has a wavelength that's too long to excite intermediary proteins, but three photons together will carry enough energy to excite a fluorescent protein when light is concentrated at the focal point.

The laser then scans repeatedly along a line in the brain. By repeatedly imaging, parallel lines add up to a two-dimensional cross section of a brain region. By repeating this process at different depths, the researchers attain a three-dimensional image of brain structures.

With the new tool, Fetcho said, researchers may now use fish that are engineered to develop a version of autism and other disorders, and watch how the disease progesses as the fish ages. These fish models could also be used to test potential treatments to see if they improve function, and how brain structure and function change if a condition improves.

"This is a step ... toward cures for some of the devastating brain disorders faced by humans," Fetcho said.

Xu's lab developed the imaging technology, while Fetcho's lab worked on the neurobiology and behavioral aspects of the study. Co-author Andrew Bass, the Horace White Professor of Neurobiology and Behavior in A&S, also provided a different fish model that is still in development, for a smaller relative of zebrafish, called Danionella dracula, which would be easier to image.

AMHERST, Mass. - As physicians and families know too well, though Alzheimer's disease has been intensely studied for decades, too much is still not known about molecular processes in the brain that cause it. Now researchers at the University of Massachusetts Amherst say new insights from analytic theory and molecular simulation techniques offer a better understanding of amyloid fibril growth and brain pathology.

As senior author Jianhan Chen notes, the "amyloid hypothesis" was promising - amyloid protein fibrils are a central feature in Alzheimer's, Parkinson's disease and other neurodegenerative diseases. "But the process is really difficult to study," he says. "For many years people thought the fibril might the harmful factor in the brain. But after billions of dollars of investment failed to deliver an Alzheimer's drug, that thinking is really questioned. We now believe that the fibril is not the toxic species, but it's the earlier forms, soluble oligomers or proto-fibrils. That's what we wanted to study."

Chen and first author Zhiguang Jia, a research scientist in Chen's computational biophysics lab, explored how building-block peptides form fibrils. "We are really proud of this work because, to the best of our knowledge, for the first time we have described the comprehensive process of how fibril growth can happen. We illustrate that the effects of disease-causing mutations often arise from the cumulative effects of many small perturbations. A comprehensive description is absolutely critical to generate reliable and testable hypothesis," he adds. Details of their multi-scale approach with many atomistic simulations are in Proceedings of the National Academy of Sciences.

Chen adds, "The process is slow and very complex. All the nonproductive pathways are usually hidden and have never been described in a comprehensive and quantitative fashion. It is like the dark side of the moon."

Chen says their model is "parameter-free and purely based on physics, with no fitting or assumptions needed. We provide a complete description of the process and the physics just comes out naturally. It's really satisfying; we feel it's a real breakthrough."

He and Jia focused first on how peptides in disordered solution behave. The process starts with peptides in a partially unfolded conformation, Chen notes. They describe both productive and non-productive aggregation processes and point out that non-productive ones can take a very long time to disengage from interactions. "It's like hiking in the woods without a path," Chen says. "It's like a maze. And if one peptide takes a mistaken pathway, it has start over and retry many, many times."

A key insight was to account for these many non-productive pathways - too many possibilities - that slow movement and cause a "kinetic bottleneck," he says. Another important insight, Chen points out, is that the "energy landscape" as biophysicists call it, is crucial. With "usual" structured proteins, in spite of their great complexity, they fold quickly because the underlying energy landscape is well structured to support quick, efficient folding.

By contrast, fibril growth occurs in a "really flat" energy landscape, he adds. "There are many, many mistakes before you fall into the hole that will lead to fibril formation." Biochemists call it "unguided search," he says, adding that "bumbling" is a good way to describe it.

Modeling and characterizing such unguided systems are extremely difficult, the biophysicist notes. "To use a simulation to predict the process, you need a complete description of the whole maze or you can never grasp it, and this is almost impossible. To describe comprehensively the search space, you must compromise resolution of peptide modeling. When you limit the resolution of the model, you'll not be able to faithfully capture the impacts of disease mutations, for example."

He says these conflicting requirements - resolution and completeness - must be satisfied at the same time. "Our approach is the first to satisfy both. This is one of our technical breakthroughs," Chen says.

Chen says a key inspiration for the multi-scale algorithm came from theoretical work from Jeremy Schmit, a collaborator and co-author of the paper from Kansas State University. "Together, we show how to achieve a description of the peptide search process at the atomic level. We demonstrate our approach by looking at how mutations in amyloid beta peptide affect fibril growth. Our results show that we can reproduce what is known about these mutants, plus peculiar non-additivity of mutations, that is observed experimentally. It means that two positions can mutate and either one will make fibril growth go faster, but if both are mutated, fibril growth goes slowly."

MINNEAPOLIS - New guidance from the American Academy of Neurology (AAN) concludes that closure of a common heart defect called a patent foramen ovale (PFO) may be recommended for some people who have had a stroke. The updated practice advisory is published in the April 29, 2020, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Closure may be considered for some people under age 60 to help prevent a second stroke, according to the practice advisory, which is endorsed by the American Heart Association/American Stroke Association, the Society for Cardiovascular Angiography and Interventions and the European Academy of Neurology.

A PFO is a channel between the right and left sides of the heart. All infants have this small flap-like opening between the two sides. In most people, this channel closes on its own by adulthood. But for about one in four people, it remains open.

"It's important to note that having a PFO is common, and that most people with PFO will never know they have it because it usually does not cause any problems," said study author Steven R. Messé, M.D., of the Perelman School of Medicine at the University of Pennsylvania, and a Fellow of the American Academy of Neurology. "However, while there is generally a very low risk of stroke in patients with PFO, in younger people who have had a stroke without any other possible causes identified, closing the PFO may reduce the risk of having another stroke better than medication alone."

The practice advisory updates a 2016 advisory that concluded there was not enough evidence to support routine PFO closure to prevent a second stroke. Since then, new studies reported that for people with stroke due to a PFO, closure in addition to taking medication to prevent blood clots, reduced the risk of future strokes better than medication alone.

In PFO closure, doctors use a catheter to place a device in the channel between the right and left sides of the heart to prevent blood flow.

For the practice advisory, clinical experts carefully reviewed the available evidence about stroke prevention in patients with a PFO who had already had an ischemic stroke, which is a stroke caused by a blockage in a blood vessel leading to reduced blood flow.

When considering PFO closure in people who have had a stroke, the practice advisory recommends that doctors with expertise in stroke to first rule out causes other than the PFO, such as hardening or a tear of the blood vessels, heart disease including abnormal heart rhythms, or an increased risk for forming clots, to ensure that PFO is the most likely cause of stroke. The practice advisory does not recommend PFO closure if another higher risk cause of stroke is identified. The advisory also recommends that patients considering closure have a consultation with an expert in PFO closure, to ensure that the procedure can be safely performed.

The practice advisory states for people younger than 60 years old who have had a stroke thought to be caused by a PFO and no other cause, doctors may recommend closure of the PFO after discussing the potential benefits, including a 3.4% reduction in the risk of a second stroke in five years, as well as the potential risks, such as a 3.9% chance of procedural complications and an increased risk of an abnormal heart rhythm called atrial fibrillation of 0.33% per year.

"The risk of a second stroke in people with PFO and no other possible causes of stroke is very low, approximately 1% per year while being treated with just medication alone," said Messé. "Also, it is difficult to determine with absolute certainty that the PFO is the cause of a person's stroke. So it is important that people with PFO are educated about the benefits and risks of PFO closure."

The advisory recommends that for people who choose to take medications alone, without PFO closure, doctors may consider prescribing aspirin or other antiplatelet drugs to prevent blood clots, or anticoagulant drugs such as warfarin, also known as blood thinners.

The benefits of a brief "social belonging" exercise completed by black students in their first year of college followed them into adulthood, with participants reporting greater career satisfaction, well-being and community involvement almost a decade later.

The long-term results of that social-belonging intervention, published in the journal Science Advances, show how important it is for colleges to help students from marginalized groups to understand that worries about belonging and experiences of social adversity are common in the transition to college, regardless of one's background, said Wake Forest psychologist and study author Shannon Brady.

"Belonging is a fundamental human need. Constantly feeling unsure of whether you belong can undermine your ability to perform up to your potential," Brady said. "The question of social belonging can consume more time and mental bandwidth for people who face negative stereotypes or discrimination because of their race.

"Students from racial-minority backgrounds enter college aware that their group is underrepresented in higher education and that how people treat them can be shaped by negative stereotypes and discrimination. This reasonably leads students to worry about whether they belong--worries that can be exacerbated when they experience social adversities, like a bad grade on a test or getting left out of a social outing."

The research team also included Drs. Geoffrey Cohen and Gregory Walton of Stanford University, who devised the social-belonging intervention; and Shoshana Jarvis of the University of California, Berkeley.

During their first year of college, black and white students were invited to participate in a one-hour, in-person intensive exercise during which they heard stories from students of various backgrounds about the difficulties they experienced in their own transition to college. The goal was to help students understand that everyday social difficulties like getting a bad grade are common and often lessen over time, especially when you reach out to professors and friends for support. The study was a randomized experiment so students completed either the social-belonging intervention version of the exercise or a control exercise, also about the transition to college, but lacking the psychological message.

Past research by Walton and Cohen had shown that black students who participated in the social-belonging intervention were more likely to email professors and consult them during office hours. At the end of college, they had better grades and were happier and healthier than the students in the control group. There was no benefit of the intervention for white students.

The researchers for the current study wondered if the benefits for black participants might persist even after they left college. So they followed up with them 7-11 years later.

"This intervention understands and addresses the nature of worries about social belonging among students in an underrepresented group," said Brady. "Those worries could affect not only college experience but also life beyond college."

In Brady's study, conducted when participants were 27 years old on average, black participants who had completed the social-belonging intervention treatment in college reported:

Greater life satisfaction. In fact, on several different measures of well-being, black adults reported better outcomes in the treatment group than in the control group.

More community involvement and leadership. Sixty-eight percent of black adults in the treatment group, but only 35 percent in the control group, reported having held at least one leadership position outside of work.

Greater satisfaction and success in their careers.

Despite its positive effects, students generally didn't remember the intervention from college or didn't attribute much of their success to it. Brady says this is appropriate. Although the intervention served as a catalyst for better life outcomes, participants themselves are the ones who took the needed actions to reach out and cultivate mentor relationships. They are the ones contributing to their jobs and volunteering in their community.

The career and well-being gains were concentrated among black participants who reported developing mentor relationships in college, an outcome that the intervention increased. Brady, a project researcher with the College Transition Collaborative, suggested that a takeaway from this study for colleges is to examine whether their campus environment fosters mentor relationships and does so equally for students from different backgrounds. Colleges might find that they need to clear away structural barriers for students to find mentors, such as prioritizing and making sure faculty have enough time to connect with students and identifying people in the residence halls, religious life and academic departments who can connect with students. But it may also mean that colleges need to understand what psychological barriers hold students back from accessing the resources that exist.

"Our research shows that the intervention is not merely about the transfer of information," she said. "It's about clearing a psychological hurdle so that student feel comfortable building relationships with professors and other mentors."

Nearly 15,000 miles of new Asian roads will be built in tiger habitat by mid-century, deepening the big cat's extinction risk and highlighting the need for bold new conservation measures now, according to a new study.

University of Michigan conservation ecologist Neil Carter and his colleagues used a recently developed global roads dataset to calculate the extent and potential impacts of existing and planned road networks across the nearly 450,000-square-mile, 13-country range of the globally endangered tiger.

Fewer than 4,000 tigers remain in the wild. They are found mainly in South Asia and Southeast Asia, regions that will experience accelerating pressure from human development in coming years.

Road construction often exacerbates all three of the main threats to tigers: prey depletion, habitat degradation and poaching.

The U-M-led study showed that existing roads are pervasive throughout tiger habitat, totaling 83,300 miles (134,000 kilometers) in Tiger Conservation Landscapes (TCLs), blocks of habitat across the animal's range that are considered crucial for recovery of the species. Carter and his co-authors called this finding "a highly troubling warning sign for tiger recovery and ecosystems in Asia."

The researchers calculated three measures--road density, distance to the nearest road and relative mean species abundance--to characterize how existing road networks influence tiger habitat. They calculated current road densities for all 76 TCLs and summarized those estimates by country and protection status.

In addition, they used published forecasts of global road expansion to calculate the length of new roads that might exist in tiger habitat by 2050, for each of the 13 tiger-range countries.

The study, scheduled for publication April 29 in Science Advances, found that:

The 83,300 miles of current road networks within tiger habitat may be decreasing the abundance of tigers and their prey by more than 20%.

43% of the area where tiger breeding occurs and 57% of the area in TCLs are within 5 km (3.1 miles) of a road, a proximity that can negatively impact tigers and their prey.

Nearly 15,000 miles of new roads will be built in TCLs by 2050, stimulated through major investment projects such as China's Belt and Road Initiative.

Road densities are, on average, 34% greater in nonprotected portions of TCLs than in strictly protected parts, indicating that road density increases with the relaxation of protection status.

Road densities varied widely across tiger-range countries. China's mean road density in TCLs is nearly eight times greater than Malaysia's, for example.

"Our analysis demonstrates that, overall, tigers face a ubiquitous and mounting threat from road networks across much of their 13-country range," said U-M's Carter, an assistant professor at the School for Environment and Sustainability.

"Tiger habitats have declined by 40% since 2006, underscoring the importance of maintaining roadless areas and resisting road expansion in places where tigers still exist, before it is too late. Given that roads will be a pervasive challenge to tiger recovery in the future, we urge decision makers to make sustainable road development a top priority."

The world's remaining tigers are concentrated in a small number of source populations--areas with confirmed current presence of tigers and evidence of breeding--across the animal's geographic range. Even a small amount of road construction could disproportionately impact tiger recovery by permanently isolating tiger populations, creating tiger "islands," according to the researchers.

Protecting tigers is a global conservation priority, exemplified by a landmark international initiative, called TX2, with the goal of doubling global tiger numbers between 2010 and 2022. And tigers are considered a conservation flagship species, a popular, charismatic animal that serves as a symbol and rallying point to stimulate conservation awareness and action.

Even so, few studies have assessed the impacts of roads on tigers and their recovery, limiting the impact of tiger conservation planning.

And most previous "road ecology" studies of tigers have focused on localized patterns of wildlife mortality or behavior associated with road design. The new study by Carter and his colleagues, in contrast, estimates road impacts on wildlife at broad scales. It is the first study to include baseline indices on the threat from existing and future roads in tiger habitat.

"This research opens the door to build partnerships at the regional scale to better mitigate existing roads and to develop greener road designs for the next century of infrastructure development," said study co-author Adam Ford, a wildlife ecologist at the University of British Columbia.

The researchers say their metrics provide tools to support sustainable road development, enabling rapid risk assessment for roads passing through tiger habitat, including roads planned as part of the Belt and Road Initiative.

The BRI is a global development strategy adopted by the Chinese government in 2013 involving infrastructure projects in dozens of countries in Asia, Europe and Africa. The rush to build major new roads throughout the forested regions of South Asia and Southeast Asia, financed through the initiative, could have severe impacts on tigers, according to Carter and his colleagues.

But the BRI could become an important partner in tiger preservation, according to the researchers, by adopting biodiversity conservation as one of its core values. That would set the stage for the BRI to plan and implement a network of protected areas and wildlife corridors to safeguard tigers from road impacts.

In a paper published today in the journal Science Translational Medicine, scientists from the Schools of Life Sciences and Chemistry at the University, have discovered that by inhibiting a molecule in patients' cells called CDK12, they can potentially develop a therapy to alleviate some of the symptoms, and help treat this incurable condition.

Myotonic dystrophy is a long-term genetic disorder that affects muscle function. It is the most common form of muscular dystrophy in adults and affects about one in 8,000 people. There is currently no treatment available.

Symptoms include gradually worsening muscle loss and weakness. Muscles often contract and are very slow to relax. Other symptoms may include cataracts, intellectual disability and heart conduction problems.

Some patients have a very mild form and others have severe form, where they are congenitally affected from birth.

This is due to the molecular underpinning of the condition, which is caused by a dynamic mutation; a triplet repeat expansion, in which three base pairs of DNA are present in different copy numbers. In the general population people have 5-30 copies of this DNA sequence.

In patients with myotonic dystrophy- this particular segment of DNA becomes bigger than it is in the general population, often with hundreds of copies of the triplet repeat.

The faulty gene produces a faulty RNA which contains the expansion sequence, (RNA is a macromolecule essential for all known forms of life which transfers information from DNA in the nucleus to the cytoplasm of a cell where it makes proteins). The faulty RNA gets stuck in the nuclei of myotonic dystrophy patients' cells, resulting in disruption to many cellular processes.

In this new study, scientists have discovered that through the inhibition of the molecule CDK12 - the additional faulty RNA disappears, and so reduces the symptoms of the condition.

David Brook, Professor of Human Molecular Genetics in the School of Life Sciences, is the lead researcher on the study, He said: "Through our research we now understand a key molecular component in the pathway of the condition and that's a target for us to try to inhibit this particular CDK12 protein which will then have beneficial effects in terms of developing a treatment.

"Transcription is the process by which RNA is made from DNA and this can require CDK12. When the repeat sequence is transcribed, it makes the faulty expansion RNA - but we think that the myotonic dystrophy patients' cells struggle to make the faulty RNA and they increase their levels of CDK12 to keep ploughing through the expansion sequence and make more of this RNA because the cell doesn't know this is toxic.

"What we've found is that our inhibitors affect the function of CDK12 and so prevent the transcription of the faulty RNA which offers a possible route to a treatment of the condition.

"We are now at the stage where we know if we can inhibit CDK12 selectively - then it's going to be a potential therapy - and now we are trying to work out how to do that."

SAN DIEGO, Calif. (April 29, 2020) -- Since there are no FDA-approved treatments for COVID-19, people may end up searching for unproven therapies. Therefore, when several high-profile figures - including President Donald Trump and Elon Musk - endorsed the use of chloroquine and hydroxychloroquine to treat COVID-19, it brought the issue of misinformation to the forefront of public discourse. How did these endorsements of an unproven treatment impact the public?

A new study published in JAMA Internal Medicine from a team of researchers at Oxford, Harvard, UC San Diego and Johns Hopkins used Americans' Google searches to track how the public began shopping for these unproven drugs soon after these high-profile endorsements. "We know that high-profile endorsements matter in advertising, so it stands to reason that these endorsements could spur people to seek out these medications" said Michael Liu, a graduate student at Oxford and the study's first author.

Estimating the Effect of Misinformation

The study used Google Trends, a public archive of aggregate Google searches, to track searches originating from the United States between February 1 and March 29, 2020 related to chloroquine and hydroxychloroquine. This time period included the first endorsement by a high-profile individual (Elon Musk on March 16), President Trump's first endorsement on March 19, and the first reported chloroquine poisoning in the US.

"We specifically wanted to know if people were looking to buy these drugs, instead of just looking to learn more about them," said Dr. John Ayers, study co-author, co-founder of the Center for Data Driven Health at the Qualcomm Institute, and Vice Chief of Innovation in the Division of Infectious Disease & Global Public Health, both at UC San Diego. The study tracked all Google searches mentioning the drugs "chloroquine" or "hydroxychloroquine" in combination with "buy", "order", "Walmart", "eBay", or "Amazon". The team then compared these phrases' search frequency over that time frame with a hypothetical scenario in which there were no high-profile endorsements, based on historical search trends for the same terms.

Searches for purchasing chloroquine were 442% higher and searches for hydroxychloroquine were 1,389% higher following their public endorsements. Moreover, the first and largest spikes in searches coincided with Musk's Twitter endorsement and Trump's first endorsement.

Even after widespread reports of a fatal chloroquine poisoning in Arizona on March 23, queries for purchasing either chloroquine or hydroxychloroquine remained elevated. Searches for chloroquine and hydroxychloroquine were 212% and 1,167% greater than expected following the first reported poisoning through the end of observation on March 29.

"In absolute terms, we estimate there were more than 200,000 total Google searches for buying these two drugs in only 14 days following high-profile endorsements. This could be evidence that thousands of Americans were interested in purchasing these drugs," said Dr. Mark Dredze, study co-author and Associate Professor at Johns Hopkins University.

The Dangerous Consequences of Misinformation

"Musk's and Trump's endorsements are especially troublesome for three reasons," said Mr. Liu. "First, these treatments have inconclusive clinical efficacy. Second, these drugs have potentially fatal side effects. Third, chloroquine-containing products such as aquarium cleaner are commercially available to the public without a medical prescription."

"As someone who has been studying health misinformation for years, we usually think misinformation spreads from unreliable health sources, online trolls, and bots. It's rare to have health misinformation coming from such high-profile figures," said Dr. Dredze.

"Even during these unprecedented circumstances, we must still practice evidence-based medicine," added Mr. Liu. "This means allowing the usual FDA approval process to run its course so the public is protected from unnecessary harms."

Combating the Consequences of Misinformation

Many health leaders and companies have done a fantastic job to help protect against the dangers of misinformation, the team notes, but more remains to be done.

"Google responded to COVID-19 by integrating an educational OneBox into search results related to the pandemic that linked millions of searchers seeking information on coronavirus to evidenced-based resources. This should be expanded to include warnings after searching for potential COVID-19 therapies so people can be directed to reliable information," said Mr. Liu. "Similarly retailers selling unapproved products that might be linked to use for COVID-19 -- and marketplaces like Amazon that coordinate these sales -- should provide appropriate warnings."

"It is also critical that regulatory agencies pivot to address COVID-19 misinformation", added Theodore Caputi, a study co-author and research fellow with the Center for Data Driven Health at the Qualcomm Institute. "The FDA should directly communicate with the public about the potential harms of unapproved therapies and create resources where the public can learn accurate information about the efficacy of chloroquine or hydroxychloroquine, and other unproven medications or products the public might be turning to."

"Our leaders and news makers need to be more mindful of the potential collateral effects of their speech," concluded Dr. Ayers. "You can't quickly put humpty dumpty back together again once you've broken him."

A team of South Korean researchers found that lactation can lower the incidence and reduce the risk of maternal postpartum diabetes. The researchers identified that lactation increases the mass and function of pancreatic beta cells through serotonin production. The team suggested that sustained improvements in pancreatic beta cells, which can last for years even after the cessation of lactation, improve mothers' metabolic health in addition to providing health benefits for infants.

Pregnancy imposes a substantial metabolic burden on women through weight gain and increased insulin resistance. Various other factors, including a history of gestational diabetes, maternal age, and obesity, further affect women's risk of progressing to diabetes after delivery, and the risk of postpartum diabetes increases more in women who have had gestational diabetes and/or repeated deliveries.

Diabetes-related complications include damage to blood vessels, which can lead to cardiovascular and cerebrovascular diseases such as heart attack and stroke, and problems with the nerves, eyes, kidneys, and many more. Since diabetes can pose a serious threat to mothers' metabolic health, the management of maternal metabolic risk factors is important, especially in the peripartum period. Previous epidemiological studies have reported that lactation reduces the risk of postpartum diabetes, but the mechanisms underlying this benefit have remained elusive.

The study, published in Science Translational Medicine on April 29, explains the biology underpinning this observation on the beneficial effects of lactation. Professor Hail Kim from the Graduate School of Medical Science and Engineering at KAIST led and jointly conducted the study in conjunction with researchers from the Seoul National University Bundang Hospital (SNUBH) and Chungnam National University (CNU) in Korea, and the University of California, San Francisco (UCSF) in the US.

In their study, the team observed that the milk-secreting hormone 'prolactin' in lactating mothers not only promotes milk production, but also plays a major role in stimulating insulin-secreting pancreatic beta cells that regulate blood glucose in the body.

The researchers also found that 'serotonin', known as a chemical that contributes to wellbeing and happiness, is produced in pancreatic beta cells during lactation. Serotonin in pancreatic beta cells act as an antioxidant and reduce oxidative stress, making mothers' beta cells healthier. Serotonin also induces the proliferation of beta cells, thereby increasing the beta cell mass and helping maintain proper glucose levels.

The research team conducted follow-up examinations on a total of 174 postpartum women, 85 lactated and 99 non-lactated, at two months postpartum and annually thereafter for at least three years. The results demonstrated that mothers who had undergone lactation improved pancreatic beta cell mass and function, and showed improved glucose homeostasis with approximately 20mg/dL lower glucose levels, thereby reducing the risk of postpartum diabetes in women. Surprisingly, this beneficial effect was maintained after the cessation of lactation, for more than three years after delivery.

Professor Kim said, "We are happy to prove that lactation benefits female metabolic health by improving beta cell mass and function as well as glycemic control."

"Our future studies on the modulation of the molecular serotonergic pathway in accordance with the management of maternal metabolic risk factors may lead to new therapeutics to help prevent mothers from developing metabolic disorders," he added.

The fast-growing cancer incidence and mortality worldwide have raised great challenges for the currently available anticancer options, which warrants the development of new therapeutic modalities based on novel antitumor mechanisms. Ferroptosis, a recently discovered form of non-apoptotic cell death, is one such candidate and has already demonstrated immense potential in clinical oncology as it provides alternative therapeutic opportunities for the management of treatment-resistant tumors. In a research study published on Science Advances, lead author Prof. Shu-Hong Yu from the University of Science and Technology of China and his collaborator Prof. Zhong Luo in Chongqing University reported a novel strategy to induce ferroptosis in target cancer cells and further amplify the ferroptotic damage for efficient tumor therapy. The nanoformulation was designed to be exclusively activated in the tumor microenvironment, which has demonstrated potent inhibition effect against multiple types of tumors while sparing healthy cells and tissues.

"Overloading tumor cells with ferrous ions could readily initiate the ferroptotic death cascade, and the complexed doxorubicin may further amplify the ferroptotic damage by providing additional reactive oxygen species to sustain the lipid peroxidation." Says Prof. Shu-Hong Yu, head of the research group in the University of Science and Technology of China. "The benefit of coordinating Fe2+ ions with doxorubicin is manifold. It could not only enhance the stability of Fe2+ ions in biological environment, but also facilitate the subsequent lipid peroxidation process to promote ferroptosis. Moreover, doxorubicin is an FDA-approved anticancer drug capable of inhibiting the topoisomerase 2 in tumor cells to prevent DNA replication, leading to complementary ferroptosis/apoptosis effect against a broad spectrum of tumor indications." Says Prof. Luo, head of the research group in Chongqing University.

The underlying molecular mechanism for the synergy between Fe2+ and doxorubicin is that doxorubicin could generate high level of intracellular ROS by activating the intracellular NADPH oxidase 4 (NOX4) in tumor cells, which may supply H2O2 to sustain the Fe2+-catalyzed lipid peroxidation.

Prof. Shu-Hong Yu also commented on one of the major challenges for the tumor targeted delivery of the Fe2+-doxorubicin complex. "The coordination complex is rapidly dissociated into free Fe2+ and doxorubicin under acidic conditions. However, both species must interact with intracellular components to take effect, necessitating further refinement of the drug delivery process."

Inspired by the recent advances in self-assembly technology, researchers from the two groups developed an intricate self-assembly-based nanoplatform for the tumor-targeted cytosolic delivery of the Fe2+-doxorubicin complex. The Fe2+-doxorubicin complex were efficiently encapsulated into amorphous calcium carbonate nanospheres in a simple one-step co-condensation process, and the surface of the drug-loaded amorphous calcium nanoparticles was modified with polyamidoamine (PAMAM) dendrimer-based tumor-microenvironment-activatable multifunctional ligands, which would remain bioinert during circulation but switch to a tumor-affinitive state upon entering the matrix metalloproteinase-2 (MMP-2)-rich tumor microenvironment. Thanks to the acid sensitivity of the amorphous calcium carbonate contents, the nanoparticle could be readily degraded in the acidic tumor lysosomes to release the Fe2+-doxorubicin complex, which could be further reverted into free doxorubicin and Fe2+ through the protonation-induced dissociation. Meanwhile, the PAMAM dendrimers could disrupt the lysosomal membrane via "proton sponge" effect and release doxorubicin and Fe2+ to the cytosol, where the H2O2 produced during doxorubicin metabolism could stimulate the ferroptotic toxicity of Fe2+ ions to tumor cells.

"We two groups have been collaborating closely on the synthesis and functionalization of biocompatible inorganic nanomaterials." Says Prof. Zhong Luo, head of the research group in Chongqing University. "Amorphous calcium carbonate nanoparticle is a very promising inorganic nanomaterial for biomedical applications. It's easy to synthesize and has tunable drug loading capability. It could also be rapidly degraded in human body and the degradation products are all non-toxic."

Dr. Menghuan Li, a senior scientist in Prof. Zhong Luo's research group, says that the nanoplatform is also a good example of repurposing old drugs for new applications. "This would greatly benefit the clinical translation of the reported nanoformulation." Says Dr. Menghuan Li.

In the future, Prof. Shu-Hong Yu and Prof. Zhong Luo hope to further simplify the synthesis procedures of the amorphous calcium carbonate-based nanoplatform and thoroughly investigate their efficacy and safety in a clinically relevant context. "This system may open up new avenues for treatment against tumors that are resistant to conventional therapies." Says Prof. Shu-Hong Yu.

New USC research reveals how APOE4, a genetic culprit for Alzheimer's disease, triggers leaks in the brain's plumbing system, allowing toxic substances to seep into the brain areas responsible for memory encoding and other cognitive functions.

The damage is linked to future problems in learning and memory, even when the disease's signature sticky plaques have not appeared. The findings suggest that the smallest blood vessels in the brain, which form the blood-brain barrier, might be a potential target for early treatment.

The study appears today in Nature.

"This study sheds light on a new way of looking at this disease and possibly treatment in people with the APOE4 gene, looking at blood vessels and improving their function to potentially slow down or arrest cognitive decline," said senior author Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC. "Severe damage to vascular cells called pericytes was linked to more severe cognitive problems in APOE4 carriers. APOE4 seems to speed up breakdown of the blood-brain barrier by activating an inflammatory pathway in blood vessels, which is associated with pericyte injury."

Scientists have long known that the APOE4 gene - which occurs in up to 14 percent of the population - increases the probability of developing Alzheimer's disease. Until now, it's been unclear how different pathologies determine the course of the disease in its early stages, or what underlying mechanisms lead to cognitive decline in APOE4 carriers.

Zlokovic's previous research shows that people who develop early memory problems also experience the most leakage in their brain's blood vessels - independent of amyloid plaque or tau, two common contributors to Alzheimer's. The leakage starts when cells called pericytes, which line the walls of blood vessels in the brain and maintain blood-brain barrier integrity, are damaged. These injured pericytes can be detected with a unique biomarker, developed by Zlokovic's lab in 2015, which shows up in cerebrospinal fluid.

For this study, scientists used standard memory tests to check the participants' cognitive abilities and their neuropsychological performance. They also used advanced neuroimaging and employed the biomarker that indicates damage to the brain's blood vessels.

In participants who had the APOE4 gene, researchers found damaged capillaries in the brain's memory center, the hippocampus and medial temporal lobe. The damage correlated with increased levels of a protein that causes inflammation, cyclophilin A - an early sign of the disease in people already at higher risk of developing Alzheimer's.

Zlokovic, who became director of the Zilkha Neurogenetic Institute in 2012, pioneered the concept that a breakdown in the blood-brain barrier contributes to cognitive impairment and dementia. The Zilkha Neurogenetic Institute opened at Keck School of Medicine in 2003 with a $20 million donation from Los Angeles businessman Selim Zilkha, who later contributed $10 million more to the effort.

Neurobiologists at KU Leuven have discovered how the signalling molecule Neuromedin U plays a crucial role in our learning process. The protein allows the brain to recall negative memories and, as such, learn from the past. The findings of their study on roundworms have been published in the journal Nature Communications.

If a certain type of food or drink has made you ill in the past, you will avoid it on future occasions. Similarly, you will avoid an uncomfortable situation that made you anxious before. This learning process, which is based on unpleasant or negative memories, is extremely important. It has fascinated researchers for years, but the molecular basis remains incompletely understood.

A new study carried out by the Division of Animal Physiology and Neurobiology of KU Leuven now sheds new light on the matter. The researchers studied the roundworm C. elegans and found that the protein Neuromedin U plays a key role in recalling negative memories. It acts as a signalling molecule allowing the neurons to communicate with each other.

Roundworms as a model organism

"The communication between brain cells is surprisingly similar between worms and humans", explains Professor Isabel Beets. "While C. elegans worms only have about 300 neurons, their brains produce many signalling molecules that are similar to those in the human brain. So, by studying C. elegans we can also learn more about the human brain."

Moreover, the worm is able to learn from past experiences, says Professor Beets. "Worms are intrinsically drawn to salt because they associate it with the presence of food. However, if they come into contact with salt when there is no food present, this results in a negative association. In other words, the worm will prefer to avoid salt."

Recalling negative memories

Inactivating the gene responsible for Neuromedin U changes the worms' behaviour, says doctoral student Jan Watteyne, lead author of the study. "We found that the protein plays a very specific role in the learning process: it ensures that the worm is able to learn from past experiences. If the worm encounters a salty environment without food, it will avoid the salt on future occasions. However, if we temporarily block Neuromedin U, the worm forgets this first experience and will be drawn to the salt again. This means that the protein doesn't help to make the association, but it does help to recall it."

"It's clear that the signalling molecule Neuromedin U plays a crucial role in learning and memory, and more specifically the retrieval of negative memories. This leads us to suspect that other similar molecules, so-called neuropeptides, also perform these specific functions."

Starting point

"Our findings in worms are a good starting point for further research into the cognitive functions of other animals. We know that Neuromedin U is also found in many other organisms and in the human brain", says Professor Liliane Schoofs. "A good knowledge of these basic mechanisms is, therefore, crucial to better understand the complex processes in the human brain."

LOUISVILLE, Ky. - Several years ago, Guillermo Rougier, Ph.D., professor in the Department of Anatomical Sciences and Neurobiology at the University of Louisville, was approached by David Krause, Ph.D., curator at the Denver Museum of Nature & Science, to help identify a complete, 3-D fossil he had discovered on Madagascar.

"When Dr. Krause showed it to me in a scientific meeting and asked me for my opinion, I said I had never seen anything like this," Rougier recalled. "This mammal has teeth for which we have no parallel."

Krause and a team of paleontologists discovered the fossil during an expedition in Madagascar and spent more than a decade working to determine where it falls in the long history of mammalian evolution and what it tells us about geography and changes in global fauna over time.

Rougier, a paleontologist who specializes in the study of the skull and teeth of ancient mammals, was intrigued and joined the international team of researchers to thoroughly analyze the fossil. Their analysis was published today in the journal Nature.

The fossil is remarkably complete, an extremely rare find for ancient mammals that lived alongside the dinosaurs. Rougier described the creature as very roughly resembling a beaver or a small capybara.

"First, it is surprising how complete it is," Rougier said. "Second, this fossil is preserved in three dimensions. When you have an animal that dies and is preserved in the rocks, the weight of the rocks on top of it flattens it out. Often it looks like a steam roller ran over it. So you might have a complete skeleton but it will be the thickness of a piece of paper - all splat out. This animal was preserved in 3-D so this gives us a wealth of detail that we very rarely have in other specimens."

The research team named the creature Adalatherium, which is translated from the Malagasy and Greek languages and means "crazy beast," a nod to its bizarre characteristics. They placed it among gondwanatherians, a poorly known group of mammals found in various locations in the Southern Hemisphere. Rougier used the teeth and skull of the animal to figure out how to relate it to other mammals that were living at the time and afterward.

"Teeth in mammals reflect their ancestry, diet and environment. In the case of Adalatherium, the morphology is so peculiar that it is hard to use the characters we normally use to establish family relationships," Rougier said. "Mammalian systematics and evolution rest heavily on dental morphology, so when you do not have teeth - or they are so strange that you do not know what to do with them (think of anteaters, whales, armadillos and pangolins) - we have a problem."

Rougier was part of the expeditions in which the first gondwanatherians were discovered in his native Argentina in the 1980s, but relatively few specimens of the group have been found since then. That makes this unusually complete discovery in Madgascar exceptionally useful in forming a more accurate picture of the enigmatic group.

Madagascar, an island off the coast of Africa, is known for unique animal species that developed in isolation over millions of years. The island broke off from India and over a period of 100 million years moved toward Africa, yet never quite arrived, allowing the animals to evolve distinctly from the larger continents.

"Adalatherium is a product of this time of isolation when Madagascar was an island, detached from India and shifting towards Africa, but before there was any African influence. So it was basically an experiment, an example of what we call island biogeography or island evolution," Rougier explained.

"Long isolated places produce very unique results in biology," Rougier said. "These fossils keep reminding us of the unexpected forms and shapes that evolution can take over long periods of time in an isolated place. Adalatherium is an animal for which we don't have any real parallels."

Although the discovery of Adalatherium is a breakthrough in understanding the gondwanatherians, there still is a great deal the scientists do not know about the animals of this time and place.

"Adalatherium is just one piece, but an important piece, in a very large puzzle on early mammalian evolution in the Southern Hemisphere," Krause said. "Unfortunately, most of the pieces are still missing."

An international research team led by the University of Hong Kong (HKU) developed a new method to accurately track the spread of COVID-19 using population flow data, and establishing a new risk assessment model to identify high-risk locales of COVID-19 at an early stage, which serves as a valuable toolkit to public health experts and policy makers in implementing infectious disease control during new outbreaks. The study findings have been published in the journal Nature today (April 29).

Dr. Jayson Jia, Associate Professor of Marketing at the Faculty of Business and Economics of HKU and lead author of the study, and his co-authors used nation-wide data provided by a major national carrier in China to track population movement out of Wuhan between 1 January and 24 January 2020, a period covering the annual Chunyun mass migration before the Chinese Lunar New Year to a lockdown of the city to contain the virus. The movement of over 11 million people travelling through Wuhan to 296 prefectures in 31 provinces and regions in China were tracked.

Differing from usual epidemiological models that rely on historical data or assumptions, the team used real-time data about actual movements focusing on aggregate population flow rather than individual tracking. The data include any mobile phone user who had spent at least 2 hours in Wuhan during the study period. Locations were detected once users had their phones on. As only aggregate data was used and no individual data was used, there was no threat to consumer privacy.

Combining the population flow data with the number and location of COVID-19 confirmed cases up to 19 February 2020 in China, Dr Jia's team showed that the relative quantity of human movement from the disease epicentre, in this case, Wuhan, directly predicted the relative frequency and geographic distribution of the number of COVID-19 cases across China. The researchers found that their model can explain 96% of the distribution and intensity of the spread of COVID-19 across China statistically.

The research team then used this empirical relationship to build a new risk detection toolkit. Leveraging on the population flow data, the researchers created an "expected growth pattern" based on the number of people arriving from the risk source, i.e. the disease epicentre. The team thereby developed a new risk model by contrasting expected growth of cases against the actual number of confirmed cases for each city in China, the difference being the "community transmission risk".

"The risk index we create is based on the following logic: If there are more reported cases than the model expected, there is a higher risk of community spread. If there are fewer reported cases than the model expected, it means that the city's preventive measures are particularly effective or it can indicate that further investigation by central authorities is needed to eliminate possible risks from inaccurate measurement," explained Dr Jia.

"What is innovative about our approach is that we use misprediction to assess the level of community risk. Our model accurately tells us how many cases we should expect given travel data. We contrast this against the confirmed cases using the logic that what cannot be explained by imported cases and primary transmissions should be community spread. " He added.

The approach is advantageous because it requires no assumptions or knowledge of how or why the virus spreads, is robust to data reporting inaccuracies, and only requires knowledge of relative distribution of human movement. It can be used by policy makers in any nation with available data to make rapid and accurate risk assessments and to plan allocation of limited resources ahead of ongoing disease outbreaks.

"Our research indicates that geographic flow of people outperforms other measures such as population size, wealth or distance from the risk source to indicate the gravity of an outbreak." said Dr Jia.

Dr Jia is currently exploring with fellow researchers the feasibility of applying this toolkit to other countries, and extending it to situations where there are multiple COVID-19 epicentres. The team is working with other national telecom carriers and seeking additional data partners.

CATONSVILLE, MD, April 29, 2020 - Job performance has long been understood to be the primary equalizing factor affecting promotions for men and women in the workplace, but research shows, women don't gain as much from the same performance improvements as men do. New research in the INFORMS journal Information Systems Research shows training plays an important part in promotions for women in the field of information technology.

"Women are more likely to be credited less for their performance improvements because of inherent biases against women in tech jobs, which may lead to management attributing performance improvements to luck or other factors rather than ability," said Nishtha Langer, one of the authors from Rensselaer Polytechnic Institute.

Women make up 57% of the U.S. labor market and 23% of computer and information technology careers. The study, "Onwards and Upwards? An Empirical Investigation of Gender and Promotions in IT Services," conducted by Langer, Ram Gopal of the Southern University of Science and Technology and Ravi Bapna of the University of Minnesota, found that women are more likely to be promoted than men, but not merely based off of performance improvements or work experience gains. Instead, oftentimes the promotion is based off training opportunities they have been involved in.

The researchers looked at data from a leading IT firm in India consisting of records of more than 7,000 employees from 2002-2007. It showed women benefit disproportionately more from training in increasing their chances of promotion but may be penalized for better performance in that their promotion likelihood is lower compared to men

"Women may see training as a credible signaling mechanism to let senior management know they are investing in themselves and are able to take on more senior roles," said Langer, a professor with the Lally School of Management at Rensselaer. "We believe training allows them to circumvent any social and structural biases that may have otherwise prevented their chances of promotions."

The researchers explain these findings by suggesting women may be more opportunistic when it comes to enrolling for courses because it can ensure faster promotions, or they may imbibe knowledge more effectively and are more adept at translating knowledge gains into promotability.