Culture

More than half of the world's population carries the bacterium Helicobacter pylori in their stomach mucosa. It often causes no problems throughout life, but sometimes it can cause inflammation, and in some cases, it can even lead to the development of stomach cancer.

Helicobacter pylori uses several "virulence" factors that allow it to survive in the stomach and can lead to the development of disease. In this issue of the journal Molecular Cell, Professor Cynthia Sharma's research team report that multiple of these factors are centrally regulated by a small RNA molecule called NikS. Prof. Sharma heads the Chair for Molecular Infection Biology II at Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany.

Among the target genes regulated by NikS are the two most important virulence factors of Helicobacter pylori as well as two encoding outer membrane proteins. In particular, the JMU researchers were able to show that NikS regulates the CagA protein, a bacterial oncoprotein that plays a central role in the development of cancer instigated by Helicobacter pylori. In addition, a protein with a so far unknown function that is released into the environment by H. pylori is also under the control of NikS.

The new findings are relevant for medicine and infectious disease research: "With the knowledge of the different functions and underlying molecular mechanisms of this small RNA during infection and the associated bacterial signaling pathways, we can gain new targets for the development of novel antimicrobial strategies," explains Cynthia Sharma.

Phase variation even in small RNA molecules

The fact that Helicobacter pylori can colonize such a hostile environment as the stomach so successfully is also due to a special genetic strategy: Like other pathogens, H. pylori uses a strategy known as phase variation to adapt as flexibly as possible to changes in its environment. Phase variation means that the bacteria constantly switch expression of a gene at random through genetic mutations, meaning that some bacteria in a population will always be ready to express the important gene when it becomes important - a sort of "bet-hedging" strategy.

Sharma's team has now been able to show for the first time that the expression of a small RNA molecule such as NikS, and not just of proteins, can also be subject to phase variation. Depending on the conditions prevailing in the stomach, different amounts of NikS might be beneficial. Levels of the small RNA can change to suit this through phase variation, thereby leading to different regulation of the disease-causing factors.

NikS helps to colonize host cells

"This mechanism could play a major role in enabling Helicobacter pylori to adapt successfully to the variable stomach environment and thus chronically colonize its host," says Sharma. In experiments, her team was able to show that NikS influences the internalization of the bacteria into host cells. In addition, the small RNA makes it easier for H. pylori to overcome epithelial barriers and, thus, might lead to better access of nutrients in deeper tissues in the stomach.

In further studies, the JMU researchers now aim to find out how the small RNA contributes to the colonization of different niches in the stomach and whether it regulates other genes that might also be involved in the bacterium's pathogenic properties.

Washington, DC (October 15, 2020) -- The National Foundation for Infectious Diseases (NFID) issued a new Call to Action report detailing the risks of co-infection with influenza (flu) and COVID-19 in adults with chronic health conditions, and the importance of flu vaccination during the 2020-2021 season. The goals of the report, The Dangers of Influenza and COVID-19 in Adults with Chronic Health Conditions, have been supported by more than 35 leading medical organizations, including the American College of Cardiology, American College of Emergency Physicians, American Diabetes Association, and American Lung Association, who are now urging their stakeholders to prioritize flu vaccination for these high-risk populations.

In the US, six in ten adults have one or more chronic health conditions, including heart disease, lung disease, and diabetes, that put them at increased risk for flu and COVID-19. For this population, related complications include the potential exacerbation of underlying health condition(s), as a result of flu-related inflammation that may persist long after the acute infection, as well as increased risk of long-term complications, such as heart attack and stroke, after experiencing acute flu or COVID-19 infection.

According to the Centers for Disease Control and Prevention (CDC), annual flu vaccination has been proven to mitigate serious flu-related complications, preventing an estimated 7.5 million flu illnesses, 3.7 million flu-associated medical visits, 105,000 flu hospitalizations, and 6,300 flu deaths in 2019-2020 alone. Yet, a recent NFID survey found that nearly one in four US adults at high risk for flu-related complications said they did not intend to get vaccinated during the 2019-2020 flu season.

"Amidst the COVID-19 pandemic, patients with chronic health conditions are facing not one, but two viruses that pose a serious threat to their health and independence," said NFID Medical Director William Schaffner, MD. "While we currently don't have an approved COVID-19 vaccine in the US, we know that annual flu vaccination can help protect these patients from hospitalization, progressive disability, and even death. It is imperative that healthcare professionals educate patients with chronic health conditions about their risks and implement strategies to increase flu vaccination rates during the COVID-19 pandemic."

In advance of an unprecedented 2020-2021 flu season, NFID convened a multidisciplinary virtual roundtable with leading experts to explore the risks of co-circulation and co-infection with flu and SARS-CoV-2 (the virus that causes COVID-19) in adults with chronic health conditions. The resulting NFID Call to Action, which summarizes the roundtable discussions, includes best practices for administering flu vaccines in conjunction with COVID-19 mitigation efforts. Despite the limited data currently available on outcomes from co-infection with the two viruses, insights from the roundtable highlighted that the impact on patients and the US public health system could be catastrophic.

"It won't take a 'bad' flu season--just 'a' flu season to make things more difficult in the ER and elsewhere in the US healthcare system," said Nicholas F. Vasquez, MD, vice chair of the Diversity, Inclusion, and Health Equity Section of the American College of Emergency Physicians. "Further strain due to the co-circulation of flu and COVID-19 could disrupt routine care and have detrimental consequences for adults with chronic health conditions."

The relationship between flu and heart disease is of particular concern during the current pandemic, as severe COVID-19 outcomes have also been associated with pre-existing cardiovascular conditions and post-infection injury to heart tissue. Over the past eight US flu seasons, nearly 47 percent of patients hospitalized for flu had heart disease, making it the most common underlying health condition associated with flu-related complications. Fortunately, flu vaccination can serve as an effective prevention strategy in these patients. One study estimated the flu vaccine is between 15 to 45 percent effective in preventing heart attacks and strokes, making it equal to or more effective than smoking cessation, statins, and antihypertensive therapy.

"I am greatly concerned for heart disease patients this flu season. It is already well-documented that heart disease is a risk factor for severe flu-related illness, but with COVID-19, we are entering a dangerous and uncharted territory," said William B. Borden, MD, professor of medicine and health policy at George Washington University, representing the American College of Cardiology. "The most important thing we can do to protect these patients is to ensure they are getting their annual flu vaccine. I am making it a point this season to strongly recommend a flu vaccine to every heart patient I see and urge my colleagues to do the same."

To help increase flu vaccination rates, the NFID Call to Action offers strategies and tactics for healthcare professionals, particularly specialists treating adults with chronic conditions during the 2020-2021 flu season, including communication methods for discussions with both patients and office staff, vaccine implementation strategies specific to the COVID-19 pandemic, and techniques for addressing vaccine misinformation.

"All healthcare professionals, including specialty care providers, have a duty to understand the risks our patients face and advocate for any preventive measure that can preserve health and save lives," said NFID President Patricia N. Whitley-Williams, MD, also representing the National Medical Association. "If you treat a patient with heart disease, lung disease, diabetes, or another chronic health condition, then you have a responsibility to insist upon annual flu vaccination."

Maunakea, Hawaii - In a surprising discovery, astronomers using two Maunakea Observatories - W. M. Keck Observatory and Canada-France-Hawaii Telescope (CFHT) - have found a globular star cluster in the Andromeda Galaxy that contains a record-breaking low amount of metals.

The stars in the cluster, called RBC EXT8, have on average 800 times less iron than our Sun and are three times more iron-poor than the previous globular cluster record-holder. RBC EXT8 is also extremely deficient in magnesium.

The study, led by Søren Larsen of Radboud University in the Netherlands, is published in today's issue of the journal Science.

"I'm amazed that this remarkable star cluster was just sitting under our noses. It is one of the brightest clusters in the Andromeda galaxy and known for decades, yet no one had checked it out in detail," said Aaron Romanowsky, a University of California Observatories (UCO) astronomer and professor at San José State University's Physics and Astronomy Department who co-authored the study. "It shows how the universe still has many surprises for us to discover. It also reminds us to check our assumptions - in this case, it was assumed enough clusters had been investigated to know how anemic they can be."

A globular cluster is a large, dense collection of thousands to millions of ancient stars that move together as a tight-knit group through a galaxy. Until now, astronomers thought large globular clusters had to contain a considerable amount of heavy elements.

Hydrogen and helium are the two main elements created after the Big Bang. Heavier elements such as iron and magnesium formed later. Finding a massive globular cluster like RBC EXT8 that is extremely impoverished in metals defies current formation models, calling into question some of our ideas about the birth of stars and galaxies in the young universe.

"Our finding shows that massive globular clusters could form in the early universe out of gas with only a small 'sprinkling' of elements other than hydrogen and helium. This is surprising because such pristine gas was thought to be in building blocks too small to form such massive star clusters," said Larsen.

"This discovery is exciting because the idea of a 'metallicity floor' for globular clusters, that must contain some minimum amount of heavy metals, underpinned so much of our thinking about how these very old star clusters formed in the early universe," said co-author Jean Brodie, Director, Centre for Astrophysics and Supercomputing at Swinburne University and Professor Emerita of Astronomy and Astrophysics at UCO. "Our finding contradicts the standard picture and that is always fun!"

The researchers observed RBC EXT8 using Keck Observatory's High-Resolution Echelle Spectrometer (HIRES) in October of 2019. The globular cluster was not originally on the program, but Larsen's team had a couple of hours of observing time left and decided to aim the Keck I telescope at the cluster, whose stellar content had not yet been studied in detail. The team made spectroscopic observations to determine RBC EXT8's metal content and used three archive images from CFHT to determine its size and estimate its mass. Their remarkable result came as quite a surprise.

"It is observationally challenging to obtain a detailed analysis of the chemical composition of globular clusters in the Andromeda Galaxy, which is in the Northern Hemisphere of the sky," said Brodie. "The HIRES capability at Keck is uniquely well-suited to meet this challenge."

In the future, the researchers hope to find more "metal-lite" globular clusters and solve the mystery about their origin.

A team of astronomers from the National Centre for Radio Astrophysics (NCRA-TIFR) in Pune, and the Raman Research Institute (RRI), in Bengaluru, has used the upgraded Giant Metrewave Radio Telescope (GMRT) to measure the atomic hydrogen content of galaxies seen as they were 8 billion years ago, when the universe was young. This is the earliest epoch in the universe for which there is a measurement of the atomic gas content of galaxies. This research has been published in the 14 October 2020 issue of the journal Nature.

Galaxies in the universe are made up mostly of gas and stars, with gas being converted into stars during the life of a galaxy. Understanding galaxies thus requires us to determine how the amounts of both gas and stars change with time. Astronomers have long known that galaxies formed stars at a higher rate when the universe was young than they do today. The star formation activity in galaxies peaked about 8-10 billion years ago and has been declining steadily till today. The cause of this decline is unknown, mostly because we have had no information about the amount of atomic hydrogen gas, the primary fuel for star formation, in galaxies in these early times.

"We have, for the first time, measured the atomic hydrogen gas content of star forming galaxies about 8 billion years ago, using the upgraded GMRT. Given the intense star formation in these early galaxies, their atomic gas would be consumed by star formation in just one or two billion years. And, if the galaxies could not acquire more gas, their star formation activity would decline, and finally cease", said Aditya Chowdhury, a Ph.D. student at NCRA-TIFR and the lead author of the study. "The observed decline in star formation activity can thus be explained by the exhaustion of the atomic hydrogen."

The measurement of the atomic hydrogen mass of distant galaxies was done by using the upgraded GMRT to search for a spectral line in atomic hydrogen. Unlike stars which emit light strongly at optical wavelengths, the atomic hydrogen signal lies in the radio wavelengths, at a wavelength of 21 cm, and can only be detected with radio telescopes. Unfortunately, this 21 cm signal is very weak, and difficult to detect from distant individual galaxies even with powerful telescopes like the upgraded GMRT. To overcome this limitation, the team used a technique called "stacking" to combine the 21 cm signals of nearly 8,000 galaxies that had earlier been identified with optical telescopes. This method measures the average gas content of these galaxies.

K. S. Dwarakanath of RRI, a co-author of the study, mentioned "We had used the GMRT in 2016, before its upgrade, to carry out a similar study. However, the narrow bandwidth before the GMRT upgrade meant that we could cover only around 850 galaxies in our analysis, and hence were not sensitive enough to detect the signal." "The big jump in our sensitivity is due to the upgrade of the GMRT in 2017", said Jayaram Chengalur, of NCRA-TIFR, a co-author of the paper. "The new wide band receivers and electronics allowed us to use 10 times more galaxies in the stacking analysis, giving sufficient sensitivity to detect the weak average 21 cm signal."

A team of researchers at Tampere University, Finland, has developed a biodegradable, transparent, flexible and fast-acting thermotherapy patch from plant leaves. The patch is compatible with flexible electronic applications. Plant material was used to reduce the amount of electronic waste.

The researchers used leaves from a Bodhi tree (Ficus religiosa). The veins of the leaves have a fractal pattern that makes the surface highly ?exible and shearable. Silver nanowires were attached to the leaf skeleton, and the surface was encapsulated in a biodegradable transparent tape.

The fractal-based design can also be used in flexible electronic applications, as it overcomes the limitations of conventional planar designs by maximizing the surface area at the microscale, or more speci?cally, maximizing the surface area to volume ratio via simple scaling. The large surface area enables effective heat transfer, allowing a rapid response time and preventing overheating. Due to the flexibile structure and uniform heating of the patch, it can also be attached to moving joints.

In orthopedics, medical thermotherapy pads are commonly used to reduce pain, improve blood circulation and decrease in?ammation. They are also used in the treatment of arthritis, stiff joints, cervical spondylosis and physical injuries.

Traditional thermotherapy pads are known to have caused burns, one reason being that some people have skin not very sensitive to heat. Part of the problem is that commercial heating pads are opaque, and users cannot see how their skin is reacting to the therapy.

As the thermotherapy patch is made entirely of plant-based materials, it can help reduce carbon footprints and electronic waste. All the materials used in the fabrication process are eco-friendly, economical, easily accessible and easy to fabricate.

"Electronc waste is a growing environmental problem worldwide. The use of biotic architectures and materials can help in the design of next-generation flexible electronic devices while also addressing e-waste problems," says Vipul Sharma, postdoctoral researcher appointed by the Academy of Finland.

Sharma works in the Bioinspired Materials and Robotics group, which is part of the BioMediTech institute of the Faculty of Medicine and Health Technology at Tampere University. The group is headed by Academy Research Fellow Veikko Sariola.

Electronics, especially flexible electronics, are increasingly integrated into medical devices, textiles, wellness trackers and other portable devices, among other things.

The concept can also be applied in various applications such as defogging/defrosting, wearable devices, industrial heat systems, sensors, thermochromic displays and micro?uidic chips.

Researchers from The University of Hong Kong's School of Biological Sciences and The Swire Institute of Marine Science, have for the first time investigated the historical presence of coral communities in the Greater Bay Area, revealing a catastrophic range collapse and loss of diversity that occurred in the last several decades.

The research, published in the prestigious journal Science Advances, looks at fossil corals collected from over 11 sites around Hong Kong, and creates the first palaeoecological baseline for coral communities in the Greater Bay Area. Led by PhD candidate and National Geographic Explorer Jonathan CYBULSKI, the team revealed what coral genera were present in the past well before major human impacts, and these include: Acropora, Montipora, Turbinaria, Psammacora, Pavona, Hydnophora, Porites, Platygyra, Goniopora and Faviids.

Every fossil tells a story

"The data we collect helps us to create a sort of fossil time machine," said Cybulski. "As corals grow naturally, parts of them will break off and fall to seafloor becoming a part of the sediment. Over time, many different layers of these coral skeletons will stack on top of one another. With a bit of effort we can core through the sediments and collect the different layers and reveal what coral communities were like through time," Cybulski explained. By using this method, the team was able to collect skeletons from over 5,000 years ago, which they determined thanks to radiocarbon dating by collaborator Dr Yusuke YOKOYAMA of the Atmosphere and Ocean Research Institute at The University of Tokyo.

When the team compared their fossil data to a modern-day dataset collected by collaborators at Baptist University - Dr Jian Wen QIU and Dr James XIE, several striking conclusions were revealed. First, there has been about a 40% decrease in the number of different corals living in Southern Hong Kong waters. Second, the greatest loss was of the ecologically important yet highly-sensitive staghorn corals (Acropora), which now only lives in an area about 50% smaller than its historic range. Finally, the greatest impact and losses of corals occurred in waters that are closest to the Pearl River Estuary in the southwest and Tolo Harbor in the Northeast. Based on the data, the teams best guess for the timing of this coral community change is conservatively within the last century, but likely within the past few decades. The overall conclusion: poor water quality driven by increased development and lack of proper treatment is presently the regions greatest threat to the survival of corals.

More hope for corals

"This trend we saw of a diversity decline and the loss of Acropora is consistent with other research in different areas of the world," Cybulski continues: "It's particularly bad news for this region, as Acropora represents the only type of coral that is complex, and creates physical space that promotes greater biodiversity. The loss of this coral is similar to losing all the big trees in a forest." However, similar to trees in a forest, Cybulski continued by saying there is hope for Hong Kong's corals through conservation efforts.

Indeed, this historical research has already played a critical role in protecting and restoring corals locally. In July earlier this year, PhD Candidate Ms Vriko YU, also of the Baker Lab at HKU, pioneered a coral restoration project in Hoi Ha Wan Marine Park (Note 1). This project aims to restore and better understand what it will take to save Hong Kong corals, and was made possible due to the water quality improvements in the bay by the local government.

Using Cybulski's historical data to infer the appropriate steps needed, the team is now returning corals such as Acropora that previously thrived in Hoi Ha, back to their proper home. To date, 100% of the reintroduced coral have survived. Furthermore, the team has documented several coral associated invertabrates at the site, showing that this restored habitat is indeed increasing biodiversity. The team feels this multi-faceted model - historical research that identifies major stress targets for local improvements - can be used by other researchers who hope to give corals their greatest chance for future survival.

15 October, Cambridge - A large international consortium of almost 200 researchers from 14 leading institutions in six countries has studied three different coronaviruses - SARS-CoV-1, SARS-CoV-2, and MERS-CoV - with the aim of finding vulnerabilities shared by these three pathogens. The research, published in the journal Science, identifies important molecular mechanisms crucial for all three coronaviruses, as well as potential drugs that could be repurposed as pan-coronavirus treatments.

The consortium included researchers at EMBL's European Bioinformatics Institute (EMBL-EBI), the Quantitative Biosciences Institute (QBI) Coronavirus Research Group (QCRG) at University of California San Francisco (UCSF), Gladstone Institutes, Institut Pasteur, Cluster of Excellence CIBSS at the University of Freiburg, the Howard Hughes Medical Institute, and other collaborators including the biotechnology companies Aetion and Synthego.

There are three known human respiratory syndromes associated with coronaviruses: severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19). These are caused by SARS-CoV-1, MERS-CoV, and SARS-CoV-2, respectively.

The scientists identified drug targets and repurposed therapeutics that may have broad-spectrum activity across all three coronavirus strains. Repurposed therapeutics with known safety profiles may offer a rapid treatment response against emerging coronavirus strains in the future.

Identifying coronavirus drug targets

Building on their previous work published in Nature and Cell, the scientists determined how viral and human proteins interact, and where viral proteins are located within host cells infected by different coronaviruses. They subsequently used this data and functional genetic screening to identify host factors that prevent coronavirus propagation. The data analysed in this study will be made freely accessible through the COVID-19 Data Portal.

"These analyses demonstrate how biological and molecular information are translated into real-world implications for the treatment of COVID-19 and other viral diseases," says Pedro Beltrao, Group Leader at EMBL-EBI. "After more than a century of relatively harmless coronaviruses, in the last 20 years we've had three coronaviruses that have been deadly. By looking across the species, we have the capability to predict pan-coronavirus therapeutics that may be effective in treating the current pandemic, which we believe will also offer promising therapeutics for a future coronavirus as well."

Another step to treat COVID-19

The researchers also performed real-world analysis on clinical data regarding COVID-19 patient outcomes. To do this, they identified molecules in human cells that could be targeted with FDA-approved therapeutics and looked to see what effect these drugs had on COVID-19 patients in the clinic. This analysis involved over 740 000 patients in the United States with known SARS-CoV-2 infection.

The data and analysis carried out in this study demonstrate how molecular information can be translated into real-world implications for the treatment of COVID-19. This study also showcases a collaborative approach that can be applied to study other infectious agents in the future.

"This far-reaching international study elucidates for the first time commonalities and, importantly, vulnerabilities, across coronaviruses, including our current challenge with the COVID-19 pandemic," says Nevan Krogan, Director of QBI and Senior Investigator at Gladstone Institutes. "In unique and rapid fashion, we were able to bridge biological and functional insights with clinical outcomes, providing an exemplary model of a differentiated way to conduct research into any disease, rapidly identify promising treatments and advance knowledge in the fields of both science and medicine. This body of work was only made possible through the collaborative efforts of senior scientific thought leaders and the teams of next-generation researchers at premier institutions across the globe."

A new article by Columbia Mailman School researchers Jeffrey Shaman and Marta Galanti explores the potential for the COVID-19 virus to become endemic, a regular feature producing recurring outbreaks in humans. They identify crucial contributing factors, including the risk for reinfection, vaccine availability and efficacy, as well as potential seasonality and interactions with other viral infections that may modulate the transmission of the virus. The article appears in the journal Science.

Shaman is a professor of environmental health sciences and director of the Columbia Mailman School Climate and Health program and a leading authority in modeling infectious disease outbreaks like SARS-CoV-2 and influenza. He was among the first to recognize the importance of asymptomatic spread and the effectiveness of lockdown measures and published highly cited estimations of the hypothetic lives saved had lockdown occurred sooner. He and Galanti, a post-doctoral research scientist in Shaman's research group, also published research finding reinfections with endemic coronaviruses are not uncommon, even within a year of prior infection.

The new paper explores one potential scenario in which immunity to SARS-CoV-2, either through infection or a vaccine, diminishes within a year--a rate similar to that seen for the endemic betacoronavirus that causes mild respiratory illness. The result would be yearly outbreaks of COVID-19. On the other hand, if immunity to SARS-CoV-2 was longer, perhaps through protection provided by immune response to infection with other endemic coronaviruses, we might experience what would initially appear to be an elimination of COVID-19 followed by a resurgence after a few years. Other contributing factors include the availability and effectiveness of a vaccine and the innate seasonality of the virus.

"Should reinfection prove commonplace, and barring a highly effective vaccine delivered to most of the world's population, SARS-CoV-2 will likely settle into a pattern of endemicity," the authors write. "Whether reinfections will be commonplace, how often they will occur, how contagious re-infected individuals will be, and whether the risk of severe clinical outcomes changes with subsequent infection remain to be understood."

Reinfection

Among those who have been infected with COVID-19, serological studies indicate that most infections, regardless of severity, induce development of some SARS-CoV-2-specific antibodies. Yet it remains unclear whether those antibodies are themselves sufficient to provide long-term "sterilizing immunity" to prevent reinfection. For many viruses, insufficient immune response, waning immunity, or mutations that allow it to "escape" immune detection can undermine or circumvent immunity and allow subsequent reinfection, although a prior infection may provide partial immunity and reduce symptom severity.

Co-Infection

Immune response to SARS-CoV-2 may be affected by whether or not someone is currently or was recently infected with another virus. Many studies prior to the pandemic show that infection with one virus can provide short-term protection--about a week--against a second infection. Other studies confirm that simultaneous respiratory virus infections are not associated with increased disease severity. While some SARS-CoV-2 coinfections have been documented, including co-infections with influenza and respiratory syncytial virus, there is insufficient data to draw conclusions. At the population level, a significant seasonal influenza outbreak could strain hospitals already dealing with COVID-19.

Seasonality

Evidence suggests COVID-19 could be more transmissible during winter. Outside the tropics, many common respiratory viruses reemerge seasonally during particular times of the year. The endemic coronaviruses (OC43, HKU1, NL63, 229E) all exhibit seasonality in temperate regions similar to influenza. Similarly, environmental conditions may also modulate SARS-CoV-2 transmissibility--not enough to preclude transmission during the early stages of the pandemic when immunity is generally low but perhaps sufficient to favor recurring seasonal transmission during winter in temperate regions, similar to influenza, once immunity increases.

SAN FRANCISCO, Calif. -- OCTOBER 15, 2020 - In a study published online in Science today, an international team of almost 200 researchers from 14 leading institutions in six countries studied the three lethal coronaviruses SARS-CoV-2, SARS-CoV-1 and MERS-CoV in order to identify commonly hijacked cellular pathways and detect promising targets for broad coronavirus inhibition. In addition, using the molecular insights gained from this multidisciplinary, systematic study of coronaviruses, the group performed an analysis of medical records of approximately 740,000 patients with SARS-CoV-2 that altered clinical outcomes in these patients to uncover approved therapeutics with potential for rapid deployment. These results demonstrate how molecular information can be translated into real-world implications for the treatment of COVID-19, an approach that can ultimately be applied to other diseases in the future.

"This far-reaching international study elucidates for the first time commonalities and, importantly, vulnerabilities, across coronaviruses, including our current challenge with the SARS-CoV-2 pandemic," said Nevan Krogan, Ph.D., director of the Quantitative Biosciences Institute (QBI) at the School of Pharmacy at UC San Francisco, senior investigator at Gladstone Institutes, and lead investigator of the study. "In unique and rapid fashion, we were able to bridge biological and functional insights with clinical outcomes, providing an exemplary model of a differentiated way to conduct research into any disease, rapidly identify promising treatments and advancing knowledge in the fields of both science and medicine. This body of work was only made possible through the collaborative efforts of senior scientific thought leaders and teams of next-generation researchers at premier institutions across the globe."

In this collaboration, academic and private sector scientists from UCSF, QBI's Coronavirus Research Group (QCRG), Gladstone Institutes, EMBL's European Bioinformatics Institute (EMBL-EBI) in Cambridge, England, Georgia State University, Icahn School of Medicine at Mount Sinai in New York, Institut Pasteur in Paris, Cluster of Excellence CIBSS at the University of Freiburg in Germany, University of Sheffield in the UK, and other institutions as well as the companies Aetion, who makes software for analysis of real-world data and genome engineering company Synthego, participated in the research.

Scientific Revelations from a Cross-Coronavirus Study of Protein Function

Building on their previous work published in both Nature and Cell, the researchers studied SARS-CoV-2, SARS-CoV-1 and MERS-CoV comprehensively, using biochemical, proteomic, genetic, structural, bioinformatic, virological and imaging approaches to identify conserved target proteins and cellular processes across coronaviruses. Leveraging the SARS-CoV-2 map of how the SARS-CoV-2 viral proteins interact with their target human host cell proteins, called an "interactome," the team built the protein-protein interaction maps for SARS-CoV-1 and MERS-CoV, highlighting several key cellular processes that are shared across all three coronaviruses. These common pathways and protein targets represent high-priority targets for therapeutic interventions for this and future pandemics.

"Working diligently since the early days of SARS-CoV-2 identification, we came together with the individual strengths of each organization to interrogate the biology and functional activities of these viruses, looking to exploit weaknesses," commented Veronica Rezelj, Ph.D., of Institut Pasteur. "In our latest study, we augmented our knowledge base by driving down into two additional coronaviruses, elucidating mechanisms across viruses that allow potential therapeutic interventions."

Structural Understanding of a Unique Interaction between viral Orf9b and Human Protein Tom70, Which Normally Supports Antiviral Immune Response

Interestingly, the team found that the mitochondrial outer membrane protein Tom70 interacts with both SARS-CoV-1 and SARS-CoV-2 protein Orf9b. Tom70 is normally involved in the activation of mitochondrial antiviral-signaling protein (MAVS) and is essential for an antiviral innate immune response. Orf9b, by binding to the substrate recognition site of Tom70, inhibits Tom70's interaction with heat shock protein 90 (Hsp90), which is key for its function in the interferon pathway and induction of apoptosis upon virus infection.

In a collaboration among more than 60 scientists in the QCRG led by Klim Verba and Oren Rosenberg at QBI, the structure of Orf9b bound to the active site of Tom70 was determined by cryoelectron microscopy (cryoEM) to a remarkable three-angstrom resolution. A noteworthy and rare finding showed that Orf9b, when by itself, forms a dimer and structurally a beta sheet, but exists as an alpha helix when bound to Tom70. Using the structural image of the bound proteins, the scientists were able to discover that a key residue in the interaction with Hsp90 is moved out of position, suggesting that Orf9b may modulate key aspects of the immune response, interferon and apoptosis signaling via Tom70. The functional significance and regulation of the Orf9b-Tom70 interaction require further experimental elucidation. This interaction, however, which is conserved between SARS-CoV-1 and SARS-CoV-2, could have value as a pan-coronavirus therapeutic target.

Pathway Targets for Potential Clinically-Approved Therapeutics

Using the three coronavirus interactomes as a guide, the team performed CRISPR and RNA interference (RNAi) knockouts of the putative host proteins of each virus and studied how loss of these proteins altered the ability of SARS-CoV-2 to infect human cells. They determined that 73 of the proteins studied were important for the replication of the virus and used this list to prioritize evaluation of drug candidates. Among these were the receptor for the inflammatory signaling molecule IL-17, which has been identified in numerous studies as an important indicator of disease severity; prostaglandin E synthase 2 (encoded by PTGES2), which functionally interacts with the Nsp7 protein in all three viruses; and sigma receptor 1, an interactor of Nsp6 from SARS-CoV-1 and SARS-CoV-2, which the group previously showed was a promising drug target in the laboratory setting.

Armed with this knowledge, the group performed a retrospective analysis of medical billing data from approximately 740,000 people who tested positive for SARS-CoV-2 or were presumptively positive.

In the outpatient setting, SARS-CoV-2-positive, new users of indomethacin, a non-steroidal anti-inflammatory drug (NSAID) that targets PGES-2, were less likely than matched new users of celecoxib, an NSAID that does not target PGES-2, to require hospitalization or inpatient services.

In the inpatient setting, again leveraging the medical billing data, the group compared the effectiveness of typical antipsychotics, namely haloperidol, which have activity against sigma receptor 1, versus atypical antipsychotics, which do not. Half as many new users of typical antipsychotics compared to new users of atypical antipsychotics progressed to the point of requiring mechanical ventilation. Typical antipsychotics can have significant adverse effects, but other sigma receptor 1-targeting drugs exist and more still are in development.

"It is critical to note that the number of patients taking each of these compounds represent small, non-interventional studies," commented Dr. Krogan. "They are nonetheless powerful examples of how molecular insight can rapidly generate clinical hypotheses and help prioritize candidates for prospective clinical trials or future drug development. A careful analysis of the relative benefits and risks of these therapeutics should be undertaken before considering prospective studies or interventions."

"These analyses demonstrate how biological and molecular information are translated into real-world implications for the treatment of COVID-19 and other viral diseases," said Pedro Beltrao, Ph.D., group leader at EMBL's European Bioinformatics Institute. "After more than a century of relatively harmless coronaviruses, in the last 20 years we have had three coronaviruses which have been deadly. By looking across the species, we have the capability to predict pan-coronavirus therapeutics that may be effective in treating the current pandemic, which we believe will also offer therapeutic promise for a future coronavirus as well."

ATLANTA--There are common vulnerabilities among three lethal coronaviruses, SARS-CoV-2, SARS-CoV-1 and MERS-CoV, such as frequently hijacked cellular pathways, that could lead to promising targets for broad coronavirus inhibition, according to a study by an international research team that includes scientists from the Institute for Biomedical Sciences at Georgia State University.

In the last 20 years, the world has faced three deadly coronaviruses: SARS-CoV-2, SARS-CoV-1 and MERS-CoV. SARS-CoV-2, the virus that causes COVID-19, has triggered a global pandemic that has already resulted in more than 37 million confirmed cases and more than one million deaths.

The study's findings, published in the journal Science, identify commonalities among coronaviruses and highlight several shared cellular processes and protein targets that should be considered as targets for therapeutic interventions for current and future pandemics.

The results were achieved by a collaboration among nearly 200 researchers from more than 14 leading institutions in six countries. Dr. Christopher Basler, professor and director of the Center for Microbial Pathogenesis in the Institute for Biomedical Sciences, led efforts at Georgia State.

Prior studies have identified more than 300 host cell proteins that can interact with SARS-CoV-2 proteins. In this study, the Basler laboratory screened each of these for their capacity to change how well the virus grows.

"The efforts identified at least 20 host genes whose protein products significantly alter how much virus is produced by infected cells," said Basler, a Georgia Research Alliance Eminent Scholar in Microbial Pathogenesis. "Those proteins represent potential targets for therapeutic intervention. For example, if a cellular protein is required for efficient virus growth, a drug that inhibits the cellular protein should slow the infection."

The multidisciplinary, global study also analyzed the medical records of about 740,000 patients with SARS-CoV-2 to identify approved therapeutics with potential for rapid deployment to treat COVID-19.

NEW YORK, October 15, 2020 -- Aetion co-authored a study published today in Science, which examined lethal coronaviruses SARS-CoV-2, SARS-CoV-1, and MERS-CoV to identify molecular characteristics of potential treatments. The study, which was led by the Quantitative Biosciences Institute at UCSF and involved nearly 200 researchers from leading institutions, applied a novel approach to evaluate molecular hypotheses by analyzing real-world data from COVID-19 patients.

Aetion researchers ran analyses on Real-Time Insights and Evidence, an instance of the Aetion Evidence Platform® with real-time health care data designed to generate evidence on prospective treatments for COVID-19.

Jeremy Rassen, Sc.D., Aetion co-founder, president, and chief science officer and one of the study's authors, made the following statement:

"These results demonstrate the value of using real-world data on COVID-19 to evaluate molecular hypotheses generated in the lab, and represent a new pathway for the use of real-world evidence to support the drug development process. While these findings are based on limited use of these medications in patients with COVID-19, we can further validate the findings with real-world or randomized evidence.

"The reach and severity of COVID-19 has created extreme urgency as researchers work to identify potential therapies and vaccines. Using near real-time healthcare data, we were able to efficiently and rigorously screen prospective interventions for COVID-19, accelerating time to insights from months to a matter of weeks. As COVID-19 treatment candidates emerge, real-world evidence -- properly generated -- has an important role in complementing clinical trials with real-world insights on usage, safety, and effectiveness across the drug lifecycle."

The team of global researchers started with lab-driven hypotheses that suggested certain medications -- those that block the coronavirus's interaction with the enzyme PGES-2 or sigma receptor 1 -- may inhibit viral replication in vivo. To evaluate whether these molecular actions reduced the severity of COVID-19 in clinical settings, Aetion identified nearly 740,000 U.S. COVID-19 patients who shortly after diagnosis began treatment with one of the potential therapies. Aetion researchers assessed whether COVID-19 severity was decreased in these patients as compared to those treated with medications without the hypothesized antiviral properties.

Aetion's analyses showed:

COVID-19-positive new users of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID) that inhibits the enzyme PGES-2, appeared substantially less likely to require hospitalization or inpatient services than matched new users of celecoxib, an NSAID that does not target PGES-2; and,

Hospitalized COVID-19-positive new users of typical antipsychotics that have activity against the sigma receptor 1 protein (such as haloperidol, chlorpromazine) were over 50% less likely to require mechanical ventilation as compared to matched new users of atypical antipsychotics (such as quetiapine, olanzapine).

Seeking to inform development of drugs effective against multiple pathogenic human coronaviruses, David E. Gordon and colleagues compared host interactions of MERS-CoV, SARS-CoV-1 and SARS-CoV-2, uncovering host pathways commonly hijacked by all three. Studying patient data showed how COVID-19 patients treated with drugs that acted against selected coronavirus host factors fared, with results that will help guide COVID-19 drug targets, the authors say. SARS-CoV-2, which causes COVID-19, is closely related to the deadly coronaviruses SARS-CoV-1 and MERS-CoV. Significant efforts are focused on developing treatments for COVID-19 but given that other highly virulent human coronavirus strains have emerged and may do so again, therapies that work across coronaviruses would also be valuable. While traditional antivirals target viral enzymes that are often subject to mutation, and thus to the development of drug resistance, targeting the host proteins required for viral replication is a strategy that can avoid resistance and lead to therapeutics with broad-spectrum activity. Focused on this approach, Gordon et al. mapped the interactions between viral and human proteins for SARS-CoV-2, SARS-CoV-1 and MERS-CoV. After expressing viral proteins in human cells, they used mass spectrometry to identify human host proteins that physically associated with each viral protein, looking for conserved interactions across all three viruses. They then used genetic screening to identify host factors that either enhanced or inhibited viral infection. To connect their in vitro molecular data to clinical information for COVID-19 patients, the authors evaluated medical billing data on nearly 740,000 patients in the United States with documented SARS-CoV-2 infection. In this cohort, they studied the use of drugs against selected targets identified in their study, asking whether patients who received them fared better than controls treated with clinically similar drugs that do not act on coronavirus host factors. Patients that received drugs focused against certain selected targets fared better in some cases, the authors report. "Replication in other patient cohorts and further work will be needed to see if there is therapeutic value in these connections," say Gordon et al., "but at the very least we have demonstrated a strategy wherein protein network analyses can be used to make testable predictions from real-world, clinical information."

By exposing larval zebrafish to a well-known optical illusion, researchers at the Max Planck Institute of Neurobiology and National Institute of Genetics in Japan have found a clever way to isolate key clusters of neurons critical to processing the direction of motion in the zebrafish's environment.

Details were published in the journal Neuron in September 2020.

Understanding how animal brains are structured and process information is an active area of research that aims to glean insights into fundamental aspects of biological computation. While human brains are seemingly the most impressive animal brain we know of, they are also extremely complex systems containing about as many neurons as there are stars in the Milky Way galaxy, with trillions of connections among them. This complexity makes studying them extremely difficult. Therefore, it is common to study smaller animal brains with much fewer neurons and interconnections, allowing researchers to probe and experiment with simpler- and easier-to-understand brain dynamics.

While smaller animals, such as the larval zebrafish, have simpler and less complex brains, the number of neurons and interconnections is still very large and thus requires researchers to devise experiments that stimulate only small portions of the brain. One way to do this is to stimulate only certain senses, such as sight or taste. This results in specific brain activity, or neural response, to specific inputs.

The research team relied on visual stimuli to study the key neurons necessary for motion processing in the larval zebrafish. By using a well-known optical illusion, the team was able to induce a motion aftereffect (MAE) response in the fish. MAE is found in most animals and arises through viewing a continuous motion in one particular direction, such as a river flowing from the right to left for an extended period of time. If the river is then shut off and the scene becomes still, the animals now sense motion in the reverse direction, from left to right, for a certain period of time following the removal of the flowing river. This indicates the optical illusion that stationary objects in the scene seem to flow in the reverse direction to the motion seen previously.

The team used MAE in the hopes that the perceived motion from the optical illusion would correspond to a smaller set of neural activity that isolates the truly necessary neurons required for motion processing.

Associate Professor Fumi Kubo, a corresponding author of the study, detailed the effectiveness of using MAE to stimulate brain activity in the zebrafish,

"By examining how these numerous neurons respond to an optical illusion, we found that only a dozen or so neurons are required for motion perception in zebrafish larvae."

Kubo and the team hope to identify how the observed activity fits in with the entire motion processing circuit and study its (inter)connections with the rest of the brain.

"The next step is to find out how these newly discovered neurons are wired within the neural circuit to exert their effect as an important node for motion processing," she said. "Are these neurons connected with visual input? What are their output targets? In a broader perspective, use of other types of optical illusions may identify new circuit elements in the visual processing."

The findings come from a cross-sectional study, published in BMJ Open, of the comments submitted to the US Food and Drug Administration (FDA) 'Proposed Regulatory Framework for Modifications to Artificial Intelligence/Machine Learning (AI/ML)-Based Software as a Medical Device (SaMD)--Discussion Paper and Request for Feedback'.

Artificial intelligence (AI) and machine learning (ML) technologies have the potential to transform health care, continually incorporating insights from the vast amount of data generated every day during the delivery of health care. Many such devices must have regulatory approval or clearance before being available for clinical practice, and in the US that regulation falls to the FDA.

The suitability of traditional medical device regulatory pathways for AI/ML have been called into question because the nature of the technology means it is continually evolving and adapting to improve performance. Under the current framework it would mean that as devices evolved they would require further review and approval, which could be time consuming and may affect patient safety and interests. The FDA has therefore proposed a new regulatory framework for modifications to AI/ML and has asked for feedback from the public to refine the regulations.

"The process for developing regulations is, roughly, to get feedback from the public on its initial proposal, make changes and draft regulations or guidance, get more feedback, and eventually finalise," said James Smith, Postdoctoral Scientist at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford and lead author of the report. "Anyone can comment but at present there is no requirement, or even recommendation, to disclose any conflicts of interest. Also, the FDA states that it looks for 'good science' in comments but it is not a requirement to incorporate it. Our goal was to look at the extent and disclosure of financial ties to industry and the use of scientific evidence."

The team analysed all 125 publicly available comments on the FDA proposal between 2 April 2019 to 8 August 2019 and found that 79 (63%) comments came from parties with financial ties to industry in the sector. For a further 29% of comments the presence or absence of financial ties could not be confirmed. The vast majority of submitted comments (86%) did not cite any scientific literature, with only 4% citing a systematic review or meta-analysis.

James said: "What concerns us about these findings is that we don't have a good idea of the impact of these ties and whether they might lead to bias in this specific context. Whether these observations about prevalence of ties hold true in the development of other regulations, we don't yet know, but there is a growing body of evidence showing the influence of industry throughout the medical research enterprise, and this paper adds to that. I hope it will highlight the need for greater transparency."

Gary Collins, Professor of Medical Statistics and a co-author of the study, added: "We were also concerned by the lack of scientific evidence used in comments, and the dominance of industry over academic commenters, despite AI/ML being a very active area of research. But we hope our findings will bring the FDA proposal to the attention of academics and encourage more of them to participate in the next round of feedback on the framework, and other regulatory frameworks, where academic input could be valuable."

Trinity College Dublin researchers have carried out the first multi-centred, international, qualitative study exploring the athlete experience (in their own words) of sporting low back pain (LBP).

LBP is common in rowers and can cause extended time out from the sport and even retirement for some athletes. Rowers from diverse settings (club and university to international standard) in two continents were included in the study.

The findings have been published in the British Journal of Sports Medicine (Thursday, 15th October 2020).

In an Irish context, rowing is currently one of our most successful sports and Rowing Ireland has 4000 registered racing members. About 50% of elite rowers in Ireland will have an episode of rowing related low back pain in a year. Australia is one of the biggest rowing nations in the world. Researchers at Curtin University in Perth, who partnered on this study are globally respected for their back-pain research.

With the evolution of professional sport, the mantra of 'win at all costs' pervades. This attitude is present even in grassroot sports. Focus has shifted from enjoyable participation to prioritising performance outcomes, leading to athletes being regarded as an asset, commodity or an investment.

A culture of toughness and resilience is encouraged but this can create confusion when it comes to reporting pain and injury which is common in sport. Athletes commonly internalise a myth that pain equates to weakness and personal failure. There is a rising interest in the influence of sporting culture on athlete's welfare; athlete abuse through mistreatment following injury is part of this.

For many sports, athletes' health is not prioritised, and this is now recognised as a form of abuse. Some athletes are not provided with a culture and environment where they can report pain and injury without negative consequences. To understand the extent of this issue and to safeguard athletes, their voice and experiences need to be heard in research.

Qualitative research allows athletes to tell their stories in their own words and is a good method of exploring their lived experience. By understanding what an athlete's experience of pain and injury is will lead to a better management of injury and better outcomes. It is likely to contribute to prevention of injury.

The key messages from the study are:

Rowers in this study felt compromised by their LBP and in many cases felt that the prevailing culture and environment did not allow them to be open and honest about their LBP for fear of exclusion.

Many felt that they had to continue competing and training when in pain. This may have increased risk of a poor outcome from their LBP as well as the poor negative emotional/mental experience that they encountered

Rowers experience of LBP can lead to isolation and can have a profound effect on their life beyond sport.

Dr Fiona Wilson, Associate Professor, Physiotherapy, School of Medicine, Trinity College said:

" This study presents a powerful message that athletes fear being judged as weak when they have pain and injury. They feel isolated and excluded when injured. They feel that there is a culture within sport that values them only when they are physically healthy. This leads athletes to hide their pain and injury which is likely to lead to poorer outcomes. Some of this may come from within the athlete and some may be reflective of cultures in some settings in the sport.

Our findings will impact not just rowers but any athlete who has experienced pain and injury, allowing their perspective to be considered. This will lead to the design of more tailored injury management programmes and will also crucially create a sporting environment where an athlete's physical health and welfare is at the core.

The findings from this study can be applied across sports and this has been reflected in the Twitter response to this paper, with athletes and clinicians from diverse sports, recognising these findings from their own experiences."