Culture

Washington, DC - May 19, 2020 -- Vaccines that protect people from infection by Streptococcus pneumoniae, which kills up to 1 million children ever year worldwide, train the immune system to recognize the pathogen's thick sugar capsule. Pneumococcus capsules are not only the active ingredient in vaccines; they're also key to the pathogen's virulence. But different strains have different capsules, which means vaccine researchers need to identify all capsule types.

This week in mBio, pneumococcus experts at the University of Alabama at Birmingham describe a newly-found capsule--the 100th to be identified since the pathogen was first discovered in the late 19th century. Microbiologist Moon Nahm, M.D., who led the study, said identifying new capsules is critical to keep up with the rapidly changing bacteria and update vaccines that can save lives.

Current pneumococcal vaccines contain 10-13 different types of capsules, and they cause a person's immune system to produce antibodies against those capsules. "If you get rid of the capsules, then the bugs cannot cause the infection," Nahm said.

But pneumococcus is a moving and constantly evolving target. As vaccines vanquish some capsules, new ones emerge that can shield the virus from the immune system. As a result, the vaccines become less effective, and the pathogen still poses a serious threat, even to immunized children. Nahm likened the pursuit of a pneumococcus vaccine to an ongoing game of whack-a-mole: Even as it protects people against known capsules, new ones pop up.

"Pneumococcus is smart," said Nahm. "It's critical for scientists to know about different capsule types." In the last decade or so, Nahm's lab in Birmingham--recognized as a reference lab by the WHO--has identified 10 new capsules. His research focuses on finding ways to make vaccines both more effective and less expensive. (The current pneumococcal vaccine costs about $100 per dose, putting it out of reach for many children in low-income countries.)

Nahm and his collaborators discovered the new capsule after being contacted by the Global Pneumococcal Sequencing (GPS) project. With funding from the Bill and Melinda Gates Foundation, GPS researchers had sequenced the genomes of more than 20,000 pneumococci strains. When those researchers found strains with capsule genes they didn't recognize, they sent the strains to Nahm's group, which identified the new and 100th capsule structure.

Notably, Nahm and his team discovered that some of the genes responsible for the new capsule came from oral streptococci, germs that live in the mouth and nose. Oral streptococci rarely cause diseases and are usually thought to be benign (though they can cause cavities). The connection suggests that the pathogenic pneumococci can capture advantageous genes from other, less harmful bacteria.

That ability may help the pathogen hide even better in the body. Nahm said diagnostic tests will need to differentiate between the genes in benign bacteria, and those in streptococci. "We have to improve our diagnostic assays in the future to avoid false positives," he said. That connection may also affect vaccine research. "If we don't know which gene is coming from which species, then we could get the vaccine design wrong."

As scientists across the globe race to develop a vaccine against SARS-CoV-2, the coronavirus that causes COVID-19, an international team led by Davide Corti at Vir Biotechnology and David Veesler at the University of Washington has been working around the clock on a complementary approach - identifying neutralizing antibodies that could be used as a preventative treatment or as a post-exposure therapy.

Their latest findings, which include data gathered at Berkeley National Laboratory's (Berkeley Lab's) Advanced Light Source (ALS), indicate that antibodies derived from SARS survivors could potently block entry of SARS-CoV-2 and other closely related coronaviruses into host cells. In a study published this week in Nature, the scientists note that the most promising candidate antibody is already on an accelerated development path toward clinical trials.

"We are very excited to have found this potent neutralizing antibody that we hope will participate in ending the COVID-19 pandemic," said Veesler.

Leveraging the immune system

Neutralizing antibodies are small proteins that inhibit pathogens by binding to the molecule or molecules that the microbe or virus uses to infect host cells. In humans and other animals, special immune cells produce neutralizing antibodies in response to infections, so that if the same pathogen is encountered again the body can eliminate it more quickly. Though natural neutralizing antibodies are typically only produced in the body for a limited time after the initial infection - past research with coronaviruses shows neutralizing antibodies last one or two years - scientists can manufacture pharmaceutical quantities of identical antibodies so long as they know the protein sequence. Mass-produced antibodies may then be given to people who do not yet have any of their own antibodies against that particular pathogen. Vaccines, on the other hand, induce the body to produce its own antibodies by introducing a carefully chosen part of a pathogen - typically a molecule from its outer surface, or a weakened or inert version of the entire pathogen.

Soon after SARS-CoV-2 emerged in late 2019, Veesler and his colleagues began screening for potential neutralizing antibodies among those identified from SARS and MERS survivors in 2003 and 2013, respectively. Veesler's structural biology team specializes in studying the protein machinery that pathogens use to infect hosts. The work is crucial for discovering what molecules can be targeted by treatments and vaccines. Their previous research on the SARS- and MERS-causing coronaviruses revealed that some neutralizing antibodies produced in response to those diseases were also effective against closely related coronaviruses. So, they suspected that several might inhibit SARS-CoV-2, which is very closely related to SARS-CoV.

The screening yielded eight antibodies that can bind to the SARS-CoV-2 spike glycoprotein - a pyramid-shaped structure on the viral surface, composed of proteins with attached carbohydrates, that facilitates entry into the host cell. Multiple studies have suggested that the spike glycoprotein is the main target for both neutralizing antibodies and vaccines, and vaccines currently in development use a piece of this structure to prime the immune system. Further tests narrowed the field to reveal one SARS-CoV antibody, called S309, that successfully neutralizes SARS-CoV-2.

Mapping the structure

To understand how this antibody hinders the spike protein, and to gather the information necessary to reproduce it, the team behind the current study used cryo-electron microscopy (cryo-EM) at the University of Washington Arnold and Mabel Beckman cryoEM center and X-ray crystallography performed at ALS beamline 5.0.2., which is managed by the Berkeley Center for Structural Biology (BCSB). The ALS - a Department of Energy (DOE) user facility open to both industry and commercial teams - is a particle accelerator called a synchrotron that produces extremely bright beams of light from infrared to X-rays. The beams are directed into beamlines to support a wide range of scientific techniques, including protein crystallography. Operation of the ALS to conduct this research was supported in part by the U.S. Department of Energy National Virtual Biotechnology Laboratory, a consortium of DOE National laboratories with core capabilities relevant to the threats posed by COVID-19, and funded under the Coronavirus Aid, Relief, and Economic Security (CARES) Act.

"David's group is a more recent user of the BCSB beamlines," said Marc Allaire, a biophysicist in Berkeley Lab's Biosciences Area and head of the BCSB. "In 2018, they used the ALS to examine the spike glycoproteins of other coronaviruses and investigate how potential antibodies bind to them, and when it became clear that SARS-CoV-2 was a threat we were able to give the team priority time to use the beamlines." The group used the ALS in early February and on March 31 they analyzed crystallized samples of S309. These samples are not infectious and posed no safety risk.

"I have been in the field for quite a while and I am still fascinated by the power of protein crystallography," Allaire added. In crystallography, a beam of X-ray light aimed at crystallized samples generates diffraction patterns. The intensities of the diffracted spots are then measured and used to reconstruct a 3D map of a molecule's atomic structure. Beamline 5.0.2 is a specialized crystallography beamline that has been in operation for 20 years supporting a broad spectrum of structural biology studies and drug discovery. "We feel privileged to be contributing to David and Davide's amazing effort and the promise of S309."

Korea Brain Research Institute (KBRI, President Pann Ghill Suh) announced on May 19 that its research team led by Dr. Jae-Yeol Joo and Dr. Key-Hwan Lim discovered, for the first time in the world, an increased specific expression of the Ube2h gene in the blood of AD patients.

The findings were published in the May Special Issue of the International Journal of Molecular Sciences (IJMS). The title and authors of the paper are as follows:

*Title: Predictive Potential of Circulating Ube2h mRNA as an E2 Ubiquitin-Conjugating Enzyme for Diagnosis or Treatment of Alzheimer's Disease

*Authors: Key-Hwan Lim(1st Author) and Jae-Yeol Joo(Corresponding Author)

To maintain homeostasis, our body continually synthesizes and degrades the protein. Once the proteins in a cell reach the end of their lifespan or become deformed, they are marked by ubiquitination* and become degraded by a cell organelle known as a proteasome*. If things go wrong during this process, unnecessary proteins accumulate within cells, causing cancer and other diseases.

* Ubiquitination: A process in which a ubiquitin (a small protein consisting of 76 amino acids) is attached to another protein

* Proteasome: A large protein complex that breaks down proteins in cells

Protein ubiquitination consists of a series of reactions for E1, E2 and E3 enzymes. In particular, there are approximately 40 E2s in the human body. Given that humans have some 30,000 genes as identified by the Human Genome Project, the number of E2s is minuscule, yet this enzyme serves as a crucial gene that controls the degradation of proteins in cells. Recently, there have been reports that the overexpression of E2s is associated with degenerative brain diseases, yet it had been unclear as to which specific enzyme was related to such cases.

The research team analyzed gene expression levels in AD patients using transcriptome analysis, and identified an increased specific expression of the Ube2h* gene (a subfamily of E2 enzymes) in their blood. The same phenomenon was also identified in the blood of AD model mouse.

* Ube2h (Ubiquitin-conjugating enzyme E2 H): A protein involved in the ubiquitination of proteins. Ube2h is one of the ubiquitin-conjugating enzymes (E2s).

On the other hand, when the suppression of the Ube2h gene expression in normal cells have not effected to the expressions of Tau and Parkin, previously known as the marker proteins of AD, showed no significant differences. This result suggests that the Ube2h gene can regulate the expression of the unknown AD related proteins for the disease and is a novel potential biomarker for AD.

This study is significant in that it has identified the correlation between ubiquitination enzymes and degenerative brain diseases while suggesting a new biomarker for the diagnosis of AD and dementia. Currently, a patent has been filed for an AD diagnosis and treatment method featuring the detection of the Ube2h gene. In the future, the research team will transfer this technology to companies to facilitate the development of dementia diagnosis kits that utilize the Ube2h gene in blood as a biomarker.

"We are working to discover AD-specific genes using next-generation sequencing (NGS) and to make use of such findings by establishing a big data set, said Dr. Jae-Yeol Joo, a senior researcher at KBRI. "For the research community, we will provide a platform for follow-up research. For industry, we hope our technology can be applied to ensure the quick and precise diagnosis and treatment of dementia."

This research was conducted as a KBRI in-house project supported by the Ministry of Science and ICT (MSIT), the Basic Research Program of the National Research Foundation of Korea (NRF) and the Individual Basic Research Program of the Ministry of Education (MOE).

DURHAM, N.C. -- In a recent study, Duke researchers tested whether a single infusion of a unit of a child's own or donor cord blood could improve social communication skills in children between the ages of 2-7 diagnosed with autism spectrum disorder.

Of the 180 children in the study, the subgroup of children without an intellectual disability showed improvements in language communication, ability to sustain attention measured via eye tracking, and increased alpha and beta EEG power, a measure of brain function.

However, those who also had an intellectual disability did not show social communication function improvement after the infusion.

The findings are publishing online May 19 in The Journal of Pediatrics.

"Cord blood contains immune modulating cells called monocytes," said Joanne Kurtzberg, M.D., Jerome S. Harris Distinguished Professor of Pediatrics, director of the Marcus Center for Cellular Cures and a pioneer in the use of cord blood treatments. "In the laboratory, these cells calm down a type of brain inflammation that can be seen in children with autism. In this study, we tested whether cord blood infusions would lessen symptoms in children with autism."

Approximately 40 percent of children with autism also have an intellectual disability, as defined as an IQ below 70, according to first author Geraldine Dawson, Ph.D., director of the Duke Institute for Brain Sciences and the William Cleland Distinguished Professor of Psychiatry and Behavioral Sciences.

More research is needed to determine why the findings in this study are different between those with and without an intellectual disability, and whether the treatment could be altered to be beneficial to more children.

"It is unclear whether the failure for children with intellectual disability is due to the short duration of the study, the outcome measures not being sensitive enough to detect change in this population or that the cord blood is actually not an effective treatment for children with autism who also have an intellectual disability," Dawson said.

"We learned a lot from this initial study," said Kurtzberg, senior author on the manuscript. "In the future, we hope to conduct a trial designed for children with autism who have intellectual disability focusing on outcome measures that can be targeted to test this group of children. We also used lessons learned from this study to design an ongoing study testing other cell therapies in older children with autism without intellectual disability."

"Overall, we are encouraged by these initial results and plan to build upon them in future studies of cellular therapies in children with autism," Kurtzberg said.

Talk about motherly instincts: Biologists at the University of Iowa have learned that female roundworms can alert their future offspring of dangers they will encounter when born, and the mothers pass on these warnings even before the offspring have been conceived.

The study shows that a mother roundworm releases a chemical called serotonin when she senses danger, such as a change in temperature, which can be harmful or even fatal to the animal. The serotonin travels from the mother's central nervous system to her unfertilized eggs, where the warning is stored, so to speak, in the egg cells and then passed to offspring after conception.

In experiments, the researchers discovered that embryos from mothers who passed along the serotonin danger signal had higher birth rate and survival success than female roundworms who had the serotonin signaling removed.

"Our study shows the mother's sensory response to danger actually protects the progeny," says Veena Prahlad, associate professor in the Department of Biology and corresponding author on the study, published in the journal eLife. "Put more simply, she seems to be protecting her potential babies before she protects her own self."

There are hints that this communication channel exists in mammals, but researchers know little about how it happens. So Prahlad and her team decided to study it in detail in roundworms. The researchers showed that the release of serotonin by maternal neurons triggers gene expression in the gonad that protects the immature egg, ensuring its survival after fertilization and even making roundworm larvae more resilient to stressors.

The team confirmed these findings by comparing birth and survival rates of roundworm larvae that received the serotonin signal to those from whom the serotonin signaling enzyme had been removed. The results showed roundworm larvae that received maternal serotonin had a 94% birth success and survival when exposed to higher temperatures compared to a 50% birth success and survival rate in higher temperatures for roundworm offspring with the serotonin signaling enzyme removed.

"So, stress in the mother is not always bad," Prahlad says. "In this case, it actually prepares the offspring for the future."

"The most exciting part of our study was the transgenerational effect," says Srijit Das, the study's first author and a postdoctoral researcher in biology. "When the mother experiences stress, the effects are communicated to the eggs such that the offspring that arise from these eggs have a higher tolerance for the same stressor."

The researchers took their findings a step further by testing the serotonin signaling mechanism with cells from a mammal. In those experiments, collaborating with Josh Weiner, professor of biology at Iowa and a co-author on the study, the researchers dosed mice neurons with serotonin. They observed the serotonin caused the same defense mechanism as in the roundworm eggs and common to all plants and animals known as the heat shock response.

This mechanism--set off by a protein called the HSF1 transcription factor, and which is activated by changes in temperature, salinity, and other stressors--triggers the production of a class of proteins called molecular chaperones, which seek out and repair or get rid of damaged proteins that have become toxic to the cell.

That means that, pending more study, serotonin may become a treatment option for activating cellular defenses against neurodegenerative disease associated with aging, including dementia, Alzheimer's disease, and Parkinson's disease.

"It took a strange journey, but it was very gratifying to see that this is something that can happen in mammalian neurons," Prahlad says. "You increase serotonin, and you can cause neurons to turn on HSF1 and increase molecular chaperones. And we know if we can increase molecular chaperones, selectively in dementias, we get a decrease in a lot of the symptoms, in toxicity and in neuronal death and dysfunction."

Prahlad plans to test whether increasing serotonin in mice would prevent them from getting dementia.

"The serotonin system is eminently druggable. It's straightforward to increase serotonin availability. You would just need to figure out dosages and frequency, but that would be our next step."

Computing - Mining for COVID-19 connections

Scientists have tapped the immense power of the Summit supercomputer at Oak Ridge National Laboratory to comb through millions of medical journal articles to identify potential vaccines, drugs and effective measures that could suppress or stop the spread of COVID-19.

A team comprising researchers from ORNL and Georgia Tech are using artificial intelligence methods designed to unearth relevant information from about 18 million available research documents. They looked for connections among 84 billion concepts and cross-referenced keywords associated with COVID-19 - such as high fever, dry cough and shortness of breath - with existing medical solutions.

"Our goal is to assist doctors' and researchers' ability to identify information about drug therapies that are already approved by the U.S. Federal Drug Administration," said ORNL's Ramakrishnan "Ramki" Kannan.

A massive subset of 6 million documents dated between 2010 and 2015 took 80 minutes, and the entire 18 million will take less than a day to run on Summit. Results will be shared with medical researchers for feedback, which will inform adjustments to improve future calculations.

Ecology - Rules to grow by

An international team of scientists found that rules governing plant growth hold true even at the edges of the world in the Arctic tundra. This new knowledge is informing predictive models that examine how critical factors such as carbon storage could change as temperatures warm.

Using the largest database of tundra plant traits yet compiled, researchers found that the strategies Arctic plants use to grow and acquire nutrients -- from "live fast and die young" to "slow and steady" -- are similar to strategies originally documented in plants that thrive in tropical and temperate regions.

"Even in the extreme conditions of the tundra, plants experience the same economic trade-offs in balancing growth and resources," said Oak Ridge National Laboratory's Colleen Iversen. "However, this study focused primarily on aboveground traits. The cold world beneath our feet is still largely unexplored."

Iversen is contributing to a similar international effort focused on the Arctic underground.

Batteries - The 3D connection

Oak Ridge National Laboratory researchers have developed a thin film, highly conductive solid-state electrolyte made of a polymer and ceramic-based composite for lithium metal batteries.

The electrolyte's novel design, which was detailed in a study, is a three-dimensional interconnected structure that can provide mechanical robustness and high lithium ionic conductivity at room temperature.

Lithium metal may potentially increase the energy density in rechargeable batteries beyond what is currently achieved by commercial lithium-ion batteries. The key to improving density lies in developing a powerful thin solid electrolyte.

Solid polymer electrolytes are flexible and low cost but have low conductivity while ceramic-based electrolytes offer better conductivity but are too brittle to process.

"We combined the advantages of both materials to form a thin composite film," ORNL's Xi Chen said. "The film was formed by partially sintering a three-dimensionally interconnected ceramic structure and the polymer filled the pores to make a robust membrane."

An accumulation of an unexpected intermediate of the peptidoglycan recycling pathway that is able to modulate the synthesis and structure of the cell wall, has been found by researchers at Umeå University, Sweden.

Most bacteria are shielded by a protective cell wall consisting of a strong yet elastic polymer called peptidoglycan. Peptidoglycan is essential for bacteria and so, it has always been in the spotlight when it comes to the development of antibiotics. Identifying new weaknesses of the bacterial cell wall as antibiotic targets is of highest international priority to fight pathogenic bacteria.

As bacteria grow, the peptidoglycan needs to grow too. In order to insert new subunits, certain enzymes must open up the peptidoglycan mesh and, as a consequence, fragments known as muropeptides are released to the extracellular environment. During an infection, these muropeptides can be detected by the host as a "danger" signals, which induce a high immune response. Therefore, in order to survive inside the host many bacterial species have devised mechanisms to re-internalize these peptidoglycan fragments, a process known as peptidoglycan recycling. However, despite it is unquestionable its value in keeping bacteria away from the host radar, peptidoglycan recycling does not exclusively happen during infection and because of this, the true biological meaning of this process has remained mysterious for microbiologists.

Felipe Cava's research group at the Molecular Infection Medicine Sweden (MIMS) studied the genetics and physiology behind the peptidoglycan-recycling pathway using as experimental model the causative agent of cholera, Vibrio cholerae. The study was performed in collaboration with Tobias Dörr (Cornell University, USA) and Matthew K. Waldor (Harvard Medical School, USA) and the results have been published in the journal Cell Reports on the 28th of April.

The scientists have revealed an unnoticed link between peptidoglycan recycling and synthesis to promote optimal cell wall assembly and composition.

The peptidoglycan recycling pathway is widely conserved amongst bacteria but this process seems to be not essential and its biological importance for the bacteria were not well-understood.

"Our lab found that the accumulation of an unexpected intermediate of the peptidoglycan recycling pathway is able to modulate the synthesis and structure of the cell wall; thus, our work provides new insights into the intersection between the peptidoglycan recycling and the de novo biosynthetic pathways," explained Felipe Cava, head of the study.

Peptidoglycan recycling is accomplished by a sequence of enzymatic steps where reinternalized muropeptides are broken down into smaller pieces. A critical step in this process is carried out by L,D-carboxypeptidases, specific enzymes that remove the terminal D-amino acid of the muropeptides. The Cava lab has found that these enzymes represent the "control checkpoint" between peptidoglycan recycling and peptidoglycan synthesis.

"A few years ago our lab, together with other colleagues, discovered that under stress conditions V. cholerae is able to produce a set of unusual amino acids (named "non-canonical D-amino acids") such as, for instance, D-Methionine. In this study we have found that muropeptides modified with these non-canonical D-amino acids are poorly recycled by LD-carboxypeptidases thereby inducing the accumulation of intermediates which play an unforeseen role in regulating the synthesis and architecture of the cell wall," explains Sara Hernández, postdoctoral researcher who conducted the study.

Besides the role in regulating cell wall synthesis and structure, extracellular peptidoglycan fragments are known to be important signals in innate immunity, organ development and behavior.

"Although most of the peptidoglycan fragments are recovered for recycling, under certain conditions bacteria can release them to the environment. It will be important to consider whether peptidoglycan fragments modified with non-canonical D-amino acids convey distinct information in inter-kingdom signaling compared to fragments with canonical chemistries," explained Felipe Cava, head of the study.

"Moreover, in microbial ecology, our findings suggest that the release the modified muropeptides into the environment could mediate interspecies peptidoglycan cross-regulation. Whether this regulation can promote cooperative or competitive behaviors is something that will need to be investigated in the future," concludes Felipe Cava.

Despite physical distance, it's possible to create proximity between family members located in different places. This is according to a study from Linköping University that has investigated how video calls bring family members together. The results show that proximity in video calls is established mainly by way of the body and the senses, e.g. by giving a digital high five.

Touching a beloved family member, or even making eye contact, is impossible online. Still, it's possible to feel close to them. Anna Martín Bylund and Linnéa Stenliden have studied the social and emotional challenges that geographical distance can create among family members who are spread out in different countries, and how longing is expressed in video calls. Their study has been published in the Journal of Multilingual and Multicultural Development.

"Our study shows that in a video call, an interaction can develop where the participants feel proximity. This interaction is enacted by way of the body and the senses, as well as other means like the camera and the technology. This research has become extra relevant in these corona times, when many of us are forced to communicate digitally", says Anna Martín Bylund, senior lecturer at Linköping University's Department of Behavioural Sciences and Learning.

The researchers have studied how three multilingual families who have moved to China communicate with their relatives in Europe. The researchers have analysed the family members' verbal and physical interaction in four online video calls. They see how the physical distance and the digital interface present various challenges, but that proximity is still established, in creative and to a degree innovative ways. The researchers have used recordings of the video calls from the participants' own mobile phones or computers, as well as from cameras installed in the rooms where the participants were located. With these separate cameras, the participants could be captured when they were not in view in the video calls.

Humour, creativity and memories create proximity

Previous research in the field has discussed whether it is possible to create proximity and togetherness digitally. It has shown that changing communication patterns affect how we move our bodies as well as how we move ourselves across national boundaries. In this study, the LiU researchers show that proximity is not a given, but that it can, to a degree, be re-created and modified by way of video calls. The study also shows that proximity is created primarily using the body and the senses, although spoken language also plays a part. In video calls, the room is very important - what appears on screen and how the body is coordinated in relation to the camera lens. In the study one can see that this suits small children without a well-developed language. Their participation is facilitated when body and space can be more important than speech.

One factor that can help build emotional proximity is humour. The camera's presence contributes to this, for instance by zooming in on different parts of the body and excluding others, leading to jokes and laughter. But proximity is also created through the participants' ability to be creative and to handle the situations that arise between themselves, the person or people they are speaking to, and the technology. An example of this is the high-five that a three-year-old in China and her grandparents give each other. But instead of one palm contacting another, the experience is replaced by skin against visual impressions, speech, and the muscle memory of a high-five. This practice produces a high-five despite everything, and togetherness between the participants.

In the conversations between the children and their relatives, memories are also evoked, which they can relate to together. In one conversation, a grandmother mentions a bag that she has given to her granddaughter, which affects the girl so much that she runs out from the conversation to get it. After the conversation is over, the girl keeps her grandmother both in her memory and in her body by holding onto the bag.

"Our study contributes insights into how technological solutions are used for everyday communication, in order to overcome distance in families with roots in different countries. The families' communication is affected by the technology, which creates specific conditions for how proximity can arise", says Linnéa Stenliden, senior lecturer at Linköping University's Department of Behavioural Sciences and Learning

Closer to far away; transcending the spatial in transnational families' online video calling is a small, qualitative study, and further research is required.

The researchers are taking the results from the study into their new project. Here they will investigate new challenges such as uncomfortable silence, which upper secondary teachers are faced with when using distance education in the age of the coronavirus.

When COVID-19 patients are critically ill, the biggest threat to their lives is lung dysfunction. If their lungs don't work, their blood can't circulate enough oxygen to the brain, the liver and other organs.

A new cohort study out of West Virginia University suggests one piece of life-support equipment--an extracorporeal membrane oxygenation machine--can be especially useful for treating some of these COVID-19 patients. But ECMO may be less helpful for COVID-19 patients who are older, who have preexisting conditions and whose heart function has deteriorated.

The findings appeared in ASAIO Journal.

An ECMO machine works by pumping someone's blood outside of their body, oxygenating it and returning it to the body. In this way, the ECMO machine gives the lungs--and sometimes the heart--time to rest and heal.

It can keep some patients alive when ventilators alone aren't enough.

The research team analyzed 32 COVID-19 patients with severely compromised lung function who were supported with ECMO.

At the time of the researchers' analysis, 22 of the patients--or 68 percent--had survived. Of those 22 patients, 17 were still on ECMO. Only five had been removed from ECMO and lived.

Those five patients had something interesting in common: they all received a kind of ECMO that supports the lungs but not the heart. None of the patients who had lung and heart ECMO support had been removed from ECMO successfully yet.

This disparity probably exists because patients who got ECMO support for both their heart and lungs were sicker to begin with, and their heart function was more compromised.

Insights like these help clinicians to "counsel patients and family members about the individualized risks and benefits of ECMO," said Jeremiah Hayanga, WVU's director of ECMO and a member of the research team.

The team also included Vinay Badhwar, the executive chair of the WVU Heart and Vascular Institute, and Jeffrey Jacobs, a consultant to HVI and a non-faculty collaborator with the School of Medicine's Department of Cardiovascular and Thoracic Surgery.

"Patients whose disease is restricted to the lung have been shown to have better survival, and this is indeed true for all indications of ECMO," Hayanga said. "When both heart and lung function are impaired, however, there is a reduction in survival, and selection in these patients warrants even greater scrutiny."

The researchers also discovered that patients who were under 65 and had fewer preexisting conditions--such as obesity, diabetes and heart disease--also fared better on ECMO than their older counterparts who had more medical issues.

"Our previously published research on national ECMO use has highlighted that patients over age 70 have drastically reduced survival," Hayanga said. "This may likely be a function of their coexisting illnesses and a lack of reserve. Indeed, the Extracorporeal Life Support Organization that provides oversight for ECMO programs around the world considers age 65 as a relative contraindication. As such, patients with advanced age require careful evaluation to ensure the benefit outweighs the risk."

Besides being relatively young, what else might improve COVID-19 patients' outcomes from ECMO?

Steroids.

Of the five patients who were successfully removed from ECMO, four had been receiving steroids through an IV. This discovery contradicts earlier findings out of China, which suggested steroids might do more harm than good.

"It is a fact that any given treatment is a single instrument in an orchestra of other treatments," Jacobs said. "The role of multiple medications in the treatment of COVID-19 remains unclear, including intravenous steroids while on ECMO, antiviral medications--like remdesivir--and antimalarial medications--like hydroxychloroquine. Ongoing research is necessary to determine the role of these medications in the treatment of patients with COVID-19, both in patients treated with ECMO and in patients not treated with ECMO."

But just because the data suggest younger, healthier COVID-19 patients--especially those prescribed steroids--may be more likely to respond well to ECMO, that doesn't mean other patients should never receive ECMO support.

"At the WVU HVI, we pride ourselves in offering individualized, patient-centric care to all patients," Hayanga said. "Our multidisciplinary team takes a very individualized approach to all patients who may benefit from ECMO support, and we fully assess the potential benefits and risks of supporting any patient with this advanced method of life support."

Patients infected with either severe acute respiratory syndrome coronavirus (SARS-CoV) or SARS-CoV-2 produce antibodies that bind to the other coronavirus, but the cross-reactive antibodies are not cross protective, at least in cell-culture experiments, researchers report May 17 in the journal Cell Reports. It remains unclear whether such antibodies offer cross protection in the human body or potentiate disease. The findings suggest that more research is needed to identify parts of the virus that are critical for inducing a cross-protective immune response.

"Since coronavirus outbreaks are likely to continue to pose global health risks in the future, the possibility of developing a cross-protective vaccine against multiple coronaviruses has been considered," says co-senior study author Chris Mok of the University of Hong Kong. "Our findings, albeit limited at present, would suggest that broadly cross-neutralizing antibodies to coronaviruses might not be commonly produced by the human immune repertoire. Moving forward, monoclonal antibody discovery and characterization will be crucial to the development of a SARS-CoV-2 vaccine in the short-term, as well as a cross-protective coronavirus vaccine in the long term."

From late 2002 to 2003, more than 8,000 people worldwide became sick with severe acute respiratory syndrome (SARS), resulting in more than 700 deaths. The virus responsible for this outbreak, known as SARS-CoV, shares approximately 80% of its genomic nucleotide sequence identity with that of SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19). The two coronaviruses also enter and infect cells the same way. During this process, the receptor-binding domain (RBD) of the spike (S) protein, which is located on the surface of the coronavirus, binds to a human cell receptor called angiotensin-converting enzyme 2, triggering viral fusion with the host cell.

Past studies have shown that protective antibodies against SARS-CoV bind to the RBD. But relatively little is known about the antibody response induced by SARS-CoV-2 infection. It is also unclear how infection with SARS-CoV influences the antibody response against SARS-CoV-2, and vice versa. Gaining insight into these questions could guide the development of an effective vaccine for SARS-CoV-2 and shed light on whether such a vaccine would also cross-protect against similar viruses.

"There are related viruses still circulating in bats, and it is unclear whether any of these may also threaten human health in future," says co-senior study author Malik Peiris of the University of Hong Kong. "As such, whether infection by one of these viruses cross-protects against another is an important question."

To address this gap in knowledge, the researchers analyzed blood samples collected from 15 SARS-CoV-2-infected patients in Hong Kong between 2 and 22 days after the onset of symptoms. Compared to blood samples from healthy controls, the five samples collected from patients 11 days after symptom onset or later had antibodies capable of binding to the RBD and other parts of the S protein on both SARS-CoV-2 and SARS-CoV.

The researchers also analyzed blood samples collected from seven patients 3 to 6 months after infection with SARS-CoV. Compared to blood samples from healthy controls, those collected from patients had antibodies capable of binding to the RBD and other parts of the S protein on SARS-CoV-2. Taken together, these findings show that infection with one coronavirus induces the production of antibodies that can bind to both RBD and non-RBD regions of the S protein on the other coronavirus.

Using cell-culture experiments, the researchers next tested whether infection with SARS-CoV-2 induces SARS-CoV-2-specific neutralizing antibodies, which protect host cells by preventing the virus from interacting with them. All 11 blood samples collected 12 days or later after the onset of symptoms had neutralizing antibodies against SARS-CoV-2. But only one blood sample had cross-neutralizing antibodies against SARS-CoV, and this response was very weak. Similarly, five blood samples from patients infected with SARS-CoV had neutralizing antibodies against this virus, but none could cross-neutralize SARS-CoV-2. Additional experiments in mice supported the findings from patients.

For now, the clinical implications remain unclear. One possibility is that cross-reactive, non-neutralizing antibodies offer cross protection against viruses in the body, even though they don't protect cultured cells. This phenomenon has been observed for other types of viruses. On the other hand, non-neutralizing antibodies against SARS-CoV-2 could enhance viral entry into cells and viral replication through a process called antibody-dependent enhancement of infection, which has been previously reported for SARS-CoV.

"Whether antibody-dependent enhancement plays a role in SARS-CoV-2 infection needs to be carefully examined in the future," says co-senior study author Ian Wilson of the Scripps Research Institute. "Addressing this question will be critical for developing a safe and effective universal coronavirus vaccine."

GRAND RAPIDS, Mich. (May 18, 2020) -- The immune system's ability to marshal specialized cells to fight off infection relies in part on tiny molecules called microRNAs, which act as a release for the "brakes" that keep cells dormant until needed, according to a new study published in the journal Cell Reports.

"These small microRNAs have an important role in balancing the on/off state of the immune system," said Connie Krawczyk, Ph.D., an associate professor in Van Andel Institute's Metabolic and Nutritional Programming group and the study's senior author. "Our findings reveal new insights into the nuts and bolts of immune function and add to a growing body of knowledge that could one day be leveraged to optimize vaccines or immunotherapies for a number of diseases."

The human body's immune responses are orchestrated by a host of different cells and components, each with their own role in fighting off pathogens, clearing out abnormal cells like cancer and jump-starting the healing process. In the absence of a threat, immune cells must remain at the ready, but in a "resting" state.

MicroRNAs are part of this intricate defense system. These small RNA molecules can rapidly regulate gene expression, which in turn directly impacts immune responses. Importantly, Krawczyk and her colleagues found that a single microRNA can be responsible for regulating multiple genes in one cell type while having little effect in another cell type, an adaptation that fine-tunes the immune response and ensures the right immune cells deploy at the right time.

For example, a specific microRNA called microRNA-9 helps determine when dendritic cells, which initiate immune responses, are active or inactive by regulating the "brakes" that help keep cells dormant. Once called to action, microRNA-9 releases the "brake," allowing access to the genes needed to put the cell to work.

"Our study really gets into the weeds of how the immune system works and how it is able to be so specific in its response to pathogens," Krawczyk said. "The findings add to the growing evidence backing the therapeutic potential of microRNAs."

COLUMBUS, Ohio - New research suggests mindfulness training may help multiple sclerosis patients in two very different ways: regulating negative emotions and improving processing speed.

People with MS who underwent the four-week mindfulness training not only improved more compared to those who did nothing - they also improved compared to those who tried another treatment, called adaptive cognitive training.

"This was a small pilot study, so we need to replicate the results, but these findings were very encouraging," said Ruchika Prakash, corresponding author of the research and associate professor of psychology at The Ohio State University.

"It is exciting to find a treatment that may be helpful in more than one way for people with multiple sclerosis."

The findings were published recently in two journal articles: primary results in Rehabilitation Psychology, and secondary analysis in Neuropsychology.

Multiple sclerosis is the most common neurological disease in young adults and is estimated to affect nearly 1 million people in the United States. It damages the central nervous system and can lead to a variety of physical, emotional and cognitive problems.

The study involved 61 people with MS who were placed in one of three groups: four-week mindfulness training, four-week adaptive cognitive training, or a waitlist control group that did nothing during the study period, but received treatment afterward.

Mindfulness-based training involves practicing paying attention to the present moment in a nonjudgmental and accepting manner, Prakash said. Among the practices in the sessions, participants learned how to focus on the breath and to do mental "body scans" to experience how their body was feeling.

In the primary analysis of the study, led by former doctoral student Brittney Schirda, the researchers wanted to find out if mindfulness training helped multiple sclerosis patients deal with a common component of the disease: problems regulating their emotions.

"Studies suggest that 30 to 50 percent of MS patients experience some form of psychiatric disorder," Prakash said. "Anything we can do to help them cope is important for their quality of life."

Study participants completed a measure of emotional regulation at the beginning and end of the study. They were asked how much they agreed with questions like "When I'm upset, I lose control over my behavior" and "I experience my emotions as overwhelming and out of control."

Results showed that people in the mindfulness training group reported they were more able to manage their emotions at the end of the study when compared to those in the other two groups.

This included the group that received adaptive cognitive training (ACT), which has shown promise for MS patients in other studies. This ACT program used computerized games to help MS patients overcome some of their cognitive deficits that make everyday functioning more difficult, such as problems with paying attention, switching focus, and planning and organizing.

"Our results provide promising evidence that mindfulness training can help MS patients deal with their emotions in a more constructive and positive way," Prakash said.

In a secondary analysis of the same study, led by doctoral student Heena Manglani, participants were assessed on their processing speed and working memory, two cognitive functions that often decline in MS patients. They also completed additional measures of cognitive functioning.

Processing speed is the time it takes a person to complete mental tasks and is related to how well they can understand and react to the information they receive.

Findings showed that after four weeks of mindfulness training, MS patients showed significantly improved processing speed based on the tests used in the study - more so than those in the other two groups.

"This is an exciting finding because processing speed is a core cognitive domain impacted in multiple sclerosis," Prakash said.

"We were somewhat surprised that this training intervention that we thought would mostly impact emotion regulation also enhanced processing speed."

Gains in working memory were similar in all three groups and there were no mindfulness-specific changes in other measures of cognitive functioning.

One of the reasons that mindfulness training is so promising is because it is an easily accessible treatment for all patients.

"Anyone can use mindfulness - even individuals with limited mobility, who often find other training techniques, like exercise training, to be more challenging," Prakash said.

Prakash and her team are now working on replicating this pilot study with a larger sample.

A new global study offers a powerful confirmation of one of the most influential frameworks in all of the behavioral sciences and behavioral economics: prospect theory, which when introduced in 1979 led to a sea change in understanding the irrational and paradoxical ways individuals make decisions and interpret risk with major impacts for science, policy, and industry. Led by a Columbia University Mailman School of Public Health researcher, the new study in 19 countries and 13 languages replicates the original study that provided the empirical basis for prospect theory. Results appear in Nature Human Behaviour.

Developed by Nobel Prize winner Daniel Kahneman and Amos Tversky, prospect theory has been called the most influential theoretical framework in all of the social sciences and popularized the concept of loss aversion, which says that people prefer small guaranteed outcomes over larger risky outcomes. The 1979 paper that launched the theory is today the most cited paper in economics and is among the most cited in psychological science.

The new study led by Kai Ruggeri, PhD, assistant professor of health policy and management, is a robust test of prospect theory at a scale commensurate with its impact--and the first to test the theory in so many countries, languages, currencies, and to focus on the generalizability of the theory. Ruggeri and colleagues used nearly identical methods to those in the original study, modifying them only to make currency values relevant for a 2019 sample within each country. Participants were presented with 17 hypothetical decisions about potential gains and losses of money. For example: If you were given $1,000 to play a game, would you accept a 50 percent chance to double your money or a 100 percent guarantee of gaining an additional $500? In all, 4,098 respondents who completed all the questions were included in the final analysis.

Results of 1979 study--now confirmed in the new global study--gave rise to prospect theory and upended orthodoxies around rational choices. Among the original study's findings: people tend to be risk-seeking when maximizing gains, but risk-averse when minimizing losses; our preferences may change depending on how they are rendered sequentially; and we tend to overweight small probabilities.

The researchers found that Kahneman and Tversky's 1979 empirical foundation for proposing prospect theory broadly replicates in all the countries they studied: they report a 90 percent replication in areas directly testing the theoretical contrasts at the heart of prospect theory. Some effects were less strong than in 1979, but the researchers say this outcome may be more a testament to the ease of accessing participants in 2019, rather than suggesting a flaw in the original study conclusions. Another possible explanation--a third of respondents were aware of the concept of loss aversion--was shown to have only a weak effect on their decisions.

The implications of prospect theory have been far-reaching, extending from economics to behavioral psychology, including health behaviors. Prospect theory has helped explain why people under-use preventive care in health, how people misunderstand risk in health, and how to frame behavioral interventions for smoking cessation in terms of losses instead of gains, among many other health-related insights.

"Our study offers compelling evidence for continuing to consider prospect theory as a viable explanation of individual behavior, and therefore valuable for informing public policy around the world, in areas from financial decision-making to population well-being," says Ruggeri.

Peggah Khorrami, MPH '20, was a unique contributor and coauthor of the study. She was the first Columbia student to participate in the Junior Researcher Programme, a global initiative for early career researchers in the behavioral sciences which is now partnering with Columbia Global Programs. Junior Researcher Programme, members were a driving force for the study. For a complete list of all 32 study authors from 27 institutions, refer to the study on Nature Human Behaviour.

Maunakea, Hawaii - New evidence shows the first-ever pictures capturing the birth of a pair of planets orbiting the star PDS 70 are in fact authentic.

Using a new infrared pyramid wavefront sensor for adaptive optics (AO) correction at W. M. Keck Observatory on Maunakea in Hawaii, a Caltech-led team of astronomers applied a new method of taking family photos of the baby planets, or protoplanets, and confirmed their existence.

The team's results are published in today's issue of The Astronomical Journal.

PDS 70 is the first known multiplanetary system where astronomers can witness planet formation in action. The first direct image of one of its planets, PDS 70b, was taken in 2018 followed by multiple images taken at different wavelengths of its sibling, PDS 70c, in 2019. Both Jupiter-like protoplanets were discovered by the European Southern Observatory's Very Large Telescope (VLT).

"There was some confusion when the two protoplanets were first imaged," said Jason Wang, a Heising-Simons Foundation 51 Pegasi b Fellow at Caltech and lead author of the study. "Planet embryos form from a disk of dust and gas surrounding a newborn star. This circumstellar material accretes onto the protoplanet, creating a kind of smokescreen that makes it difficult to differentiate the dusty, gaseous disk from the developing planet in an image."

To help provide clarity, Wang and his team developed a method to disentangle the image signals from the circumstellar disk and the protoplanets.

"We know the disk's shape should be a symmetrical ring around the star whereas a planet should be a single point in the image," said Wang. "So even if a planet appears to sit on top of the disk, which is the case with PDS 70c, based on our knowledge of how the disk looks throughout the whole image, we can infer how bright the disk should be at the location of the protoplanet and remove the disk signal. All that's left over is the planet's emission."

The team snapped images of PDS 70 with the Near-Infrared Camera (NIRC2) on the Keck II telescope, marking first science for a vortex coronagraph installed in NIRC2 as part of a recent upgrade, combined with the Observatory's upgraded AO system consisting of a new infrared pyramid wavefront sensor and real-time control computer.

"The new infrared detector technology used in our pyramid wavefront sensor has dramatically improved our ability to study exoplanets, especially those around low-mass stars where planet formation is actively occurring," said Sylvain Cetre, software engineer at Keck Observatory and one of the lead developers of the AO upgrade. "It will also allow us to improve the quality of our AO correction for harder to image targets like the center of our galaxy."

This project benefited from the innovative infrared sensor that measures distortions in light caused by the Earth's atmosphere.

"New technology is a science multiplier," says Peter Kurczynski, Program Director at the National Science Foundation, which contributed funding to this project. "It enables investigations that were never before possible."

AO is a technique used to remove the atmospheric blurring that distorts astronomical images. With the new infrared pyramid wavefront sensor and real-time controller installed, Keck Observatory's AO system is able to deliver sharper, more detailed images.

"The PDS 70 imagery Jason's team captured was among the first tests of the scientific quality produced by Keck's pyramid wavefront sensor," said AO scientist Charlotte Bond, who played a key role in the design and installation of the technology. "It's exciting to see just how precise the new AO system corrects for the atmospheric turbulence of dusty objects like the young stars where protoplanets are expected to reside, allowing for the clearest, sharpest view of baby versions of our solar system."

AURORA, Colo. (May 18, 2020) - Researchers from the University of Colorado School of Medicine have identified a new way that cells in the central nervous system regenerate and repair following damage.

In an article published in the current issue of Nature Neuroscience, scientists from CU found that precisely-timed motor learning stimulates cellular processes to improve recovery after damage to oligodendrocytes, cells that are critical for healthy neurologic function throughout life.

The study uses advanced microscopy and mouse models of multiple sclerosis (MS) to evaluate oligodendrocytes and their precursor cells to better understand how they can be harnessed to restore neuronal function following injury.

"Tissue regeneration following injury or disease is a long sought-after goal, particularly in the adult nervous system," said Ethan G. Hughes, PhD, assistant professor of Cell and Developmental Biology at the CU School of Medicine and a Boettcher Investigator.

Of particular interest in this study, Hughes and his colleagues found that mature oligodendrocytes are able to contribute to repair of the nervous system by generating new myelin sheaths. Myelin sheaths surround nerve fibers and speed transmission of nerve impulses to and from the brain. Identifying the contribution of mature oligodendrocytes to this process is a breakthrough finding that challenges existing scientific orthodoxy.

Hughes and his colleagues found that behavioral training in mice promoted the regeneration of myelin sheaths from newly formed and mature oligodendrocytes to aid in the repair of damage of the nervous system.

Their findings offer a potential new target for therapeutic interventions for patients with neurologic disability, such as those caused by MS, which is a progressive, degenerative disease that affects the ability of the brain to communicate with the rest of the body.

Hughes was awarded a Boettcher Foundation Webb-Waring Biomedical Research Award in 2016 and research grants from the Conrad N. Hilton Foundation, National Multiple Sclerosis Society, National Institutes of Neurological Disorders and Stroke, and Whitehall Foundation to support his laboratory's work. This work was done in collaboration with the laboratory of Cristin Welle, PhD, associate professor of Neurosurgery and Physiology and Biophysics at the CU School of Medicine and a fellow Boettcher Investigator. The current study by Hughes and his colleagues shows that motor learning improves recovery from demyelinating injury through enhanced remyelination.