Culture

In a new study, researchers report the structure of remdesivir - an antiviral drug that has shown promise against the SARS-CoV-2 virus in lab studies and early clinical trials - bound to both a molecule of RNA and to the viral polymerase. The new structural information illuminates the mechanism that remdesivir uses to interrupt RNA replication and shut down viral reproduction - and may inform efforts to develop new and more potent therapies that employ a similar mechanism. As the enzyme that catalyzes the synthesis of viral RNA for SARS-CoV-2, thus playing a central role in its replication, the polymerase is a primary target for fighting the virus. Prior work had reported the structure of the polymerase - an RNA-dependent RNA polymerase - using cryo-electron microscopy (cryo-EM). Wanchao Yin and colleagues took this further by again imaging the polymerase, which consists of four subunits - nsp12, nsp7, and two units of nsp8 - using cryo-EM at 2.8 angstrom resolution, obtaining results consistent with the previously determined structure. They then imaged a complex of the polymerase bound to both an RNA template and to a molecule of remdesivir, using cryo-EM at 2.5 angstrom resolution. In its active form, remdesivir mimics the structure of adenosine, a nucleoside that is incorporated into RNA during replication. When the drug, instead of a nucleoside, is added to a new RNA molecule it blocks further synthesis of viral RNA. The detailed cryo-EM structural information enabled Yin et al. to pinpoint the precise residues of the polymerase that interact with both the RNA template and remdesivir. These insights, in turn, will inform efforts to design more effective therapies that also mimic nucleosides to disrupt viral replication, and may lead to better understanding of existing nucleoside mimic drugs such as EIDD-2801, ribavirin, galidesivir, and favipiravir, the authors suggest.

Researchers from the Hubrecht Institute in Utrecht, Erasmus MC University Medical Center Rotterdam, and Maastricht University in the Netherlands have found that the coronavirus SARS-CoV-2, which causes COVID-19, can infect cells of the intestine and multiply there. Using state-of-the-art cell culture models of the human intestine, the researchers have successfully propagated the virus in vitro, and monitored the response of the cells to the virus, providing a new cell culture model for the study of COVID-19. These findings could explain the observation that approximately one third of COVID-19 patients experience gastrointestinal symptoms such as diarrhea, and the fact that the virus often can be detected in stool samples. The results of this study were published in the scientific journal Science on the 1st of May 2020.

Patients with COVID-19 show a variety of symptoms associated with respiratory organs - such as coughing, sneezing, shortness of breath, and fever - and the disease is transmitted via tiny droplets that are spread mainly through coughing and sneezing. One third of the patients however also have gastrointestinal symptoms, such as nausea and diarrhea. In addition, the virus can be detected in human stool long after the respiratory symptoms have been resolved. This suggests that the virus can also spread via so-called "fecal-oral transmission".

Though the respiratory and gastrointestinal organs may seem very different, there are some key similarities. A particularly interesting similarity is the presence of the ACE2 receptor, the receptor through which the COVID-19 causing SARS-CoV-2 virus can enter the cells. The inside of the intestine is loaded with ACE2 receptors. However, until now it was unknown whether intestinal cells could actually get infected and produce virus particles.

Intestinal organoids

Researchers from the Hubrecht Institute, Erasmus MC and Maastricht University set out to determine whether the SARS-CoV-2 virus can directly infect the cells of the intestine, and if so, whether it can replicate there as well. They used human intestinal organoids: tiny versions of the human intestine that can be grown in the lab. Hans Clevers (Hubrecht Institute): "These organoids contain the cells of the human intestinal lining, making them a compelling model to investigate infection by SARS-CoV-2."

Infection of intestinal cells

When the researchers added the virus to the organoids, they were rapidly infected. The virus enters a subset of the cells in the intestinal organoids, and the number of cells that are infected increases over time. Using electron microscopy, an advanced way to visualize different components of the cell in great detail, the researchers found virus particles inside and outside the cells of the organoids. Peter Peters (Maastricht University): "Due to the lockdown, we all studied virtual slides of the infected organoids remotely from home."

The researchers investigated the response of the intestinal cells to the virus with RNA sequencing, a method to study which genes are active in the cells. This revealed that so-called interferon stimulated genes are activated. These genes are known to combat viral infection. Future work will focus on these genes more carefully, and on how they could be used to develop new treatments.

The researchers also cultured the organoids in different conditions that result in cells with higher and lower levels of the ACE2 receptor, through which SARS-CoV-2 can enter the cells. To their surprise, they found that the virus infected cells with both high and low levels of the ACE2 receptor. Ultimately, these studies may lead to new ways to block the entry of the virus into our cells.

Implications

Bart Haagmans (Erasmus MC): "The observations made in this study provide definite proof that SARS-CoV-2 can multiply in cells of the gastrointestinal tract. However, we don't yet know whether SARS-CoV-2, present in the intestines of COVID-19 patients, plays a significant role in transmission. Our findings indicate that we should look into this possibility more closely." The current study is in line with other recent studies that identified gastrointestinal symptoms in a large fraction of COVID-19 patients and virus in the stool of patients free of respiratory symptoms. Special attention may be needed for those patients with gastrointestinal symptoms. More extensive testing using not only nose and throat swabs, but also rectal swabs or stool samples may thus be needed.

In the meantime, the researchers are continuing their collaboration to learn more about COVID-19. They are studying the differences between infections in the lung and the intestine by comparing lung and intestinal organoids infected with SARS-CoV-2.

A team of Chinese scientists have reported the high-resolution cryo-EM structure of Remdesivir-bound RNA replicase complex from SARS-CoV-2, the infective virus of COVID-19.

The research, published online in Science on May 1, was conducted by Prof. XU Huaqiang and Prof. XU Yechun from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences (CAS), Prof. ZHANG Yan from the Zhejiang University School of Medicine, Prof. ZHANG Shuyang from Peking Union Medical College and Chinese Academy of Medical Sciences, and their collaborators.

COVID-19 has spread rapidly around the world and is an ongoing humanitarian crisis. Many countries are now facing tremendous challenges in the fight against SARS-CoV-2. Finding an effective treatment is a very urgent matter.

SARS-CoV-2 is a positive-strand RNA virus that mainly infects human cells through the mucosal system. The massive replication of the virus requires the rapid synthesis of its genetic RNA. This process is mediated by a multi-subunit replication transcription complex composed of multiple non-structural proteins (nsp) of the virus. The core element is the replicase complex, which is the core component of coronavirus replication. Numerous nucleoside drugs targeting replicase are currently under clinical testing, including Remdesivir.

After 46 days of hard work, the scientists were able to elaborate the replicase-targeting mechanism underlying the antiviral efficacy of these nucleoside drugs. Their study reports the cryo-EM structure of the SARS-CoV-2 replicase both in the apo form at 2.8 Å resolution and in complex with a template-primer RNA and Remdesivir at 2.5 Å resolution. The overall conformation of the complex structure is very similar to that of the apo form, with the identical structures at the core catalytic active site. Comprehensive analysis of the structures showed that the SARS-CoV-2 replicase complex is a very efficient enzyme. During RNA extension, conformational change is small, which also explains the highly contagious nature of SARS-CoV-2.

The replicase complex recognizes RNA - but not DNA - through a sequence-independent binding way. The structure of the complex explains how Remdesivir enters the replication active site and covalently links with the viral genome, thereby inhibiting virus replication.

The residues involved in RNA binding as well as those comprising the catalytic active site are highly conserved among most RNA viruses. This shows the conservative mechanism of the replicase complex during gene replication and suggests it may be possible to develop broad spectrum antiviral inhibitors.

The structures described in this study reveal potential binding patterns that offer theoretical support for the design of more powerful, efficient and specific anti-SARS-CoV-2 drugs. In this way, they provide a basis for the design of the antiviral drugs, which are so urgently needed to fight the COVID-19 crisis.

CHAMPAIGN, Ill. -- In regenerative medicine, an ideal treatment for patients whose muscles are damaged from lack of oxygen would be to invigorate them with an injection of their own stem cells.

In a new study published in the journal ACS Nano, researchers at the University of Illinois at Urbana-Champaign demonstrated that "nanostimulators" - nanoparticles seeded with a molecule the body naturally produces to prompt stem cells to heal wounds - can amp up stem cells' regenerative powers in a targeted limb in mice.

"We wanted to utilize the natural functions of the stem cells and the stimulating factors to address muscle ischemia locally," said study leader Hyunjoon Kong, a Robert W. Schafer Professor of Chemical and Biomolecular Engineering at Illinois.

Muscle ischemia, or damage to muscle from limited oxygen or blood supply, can result from multiple causes, such as injury to a limb or peripheral artery disease. Stem cells derived from a patient's own fat tissue are known to produce factors that prompt new blood vessels to grow into the damaged muscle, restoring oxygen and nutrients, and to modulate inflammation in the damaged tissues. However, in vivo experiments have shown limited benefits, as the stem cells' activity seems to decline after injection into the muscle.

A molecule naturally produced in the body called tumor necrosis factor alpha can spur the stem cells to secrete more of the desired factors. Other studies have tried incubating the cells with TNF-alpha before injection, but the effects fade quickly, Kong said.

The Illinois team decided to try tethering the TNF-alpha directly to the stem cells, creating nanostimulators - nanoparticles laced with TNF-alpha. The nanoparticles bind to a receptor on the surface of the stem cells, providing localized, targeted and extended delivery of TNF-alpha.

"The primary benefit of stem cells toward tissue regeneration is not necessarily the ability for the cells to replace lost tissue, but to release beneficial growth factors and cytokines that assist in the process," said study co-author Marni Boppart, a professor of kinesiology and community health. "The nanostimulators allow cells to release the beneficial factors longer than they would otherwise. This provides a significant advantage, particularly when cells are transplanted into injured, diseased or aged tissues."

The researchers tested their approach on mice with surgically induced ischemia in one of their hind legs. They isolated the stem cells from fat tissue, mixed them with the nanostimulators and injected them locally to the mice's affected legs.

The researchers saw increased blood flow and oxygen levels in the ischemic legs. They also witnessed improvements in mobility - the treated mice could walk longer distances and their legs were stronger.

"We propose that this method is better than methods that require chemical preconditioning, which can affect the viability of the stem cells, take 24 hours or more of culturing and have limited-time effects," Kong said. "Our idea is to collect adipose tissue in the operating room, separate the stem cells, mix in the nanostimuators and reinject them to the patient - all in one procedure."

The researchers caution that further work is necessary to optimize the conditions for stem cell harvesting and preparation, and to study the effects over longer terms.

"Peripheral artery disease can cause debilitating pain and long-term disability. Unfortunately, there are no consistently effective treatments for this condition," Boppart said. "This study is important because it demonstrates the capacity for modified stem cells to effectively treat PAD in a preclinical model, representing a step closer toward relieving pain in humans."

A study of deforestation in Colombia by researchers from The University of Queensland has revealed some valuable insights which could be used to help slow deforestation in areas around the globe.

PhD student Pablo Negret led an effort to compare the effectiveness of protected areas in Colombia with otherwise similar non-protected sites between 2000 and 2015.

"In Colombia, there has been constant deforestation within protected areas during this 15-year period," Mr Negret said.

"This is mainly due to a lack of capacity to control illegal exploitation of resources in these areas.

"However, there was around 40 per cent less deforestation in protected areas when compared to similar areas without protection," Mr Negret said.

Despite poorer outcomes in some areas, it was clear to the researchers that most protected areas slowed deforestation.

"We also looked at regional differences and found that protected areas in the Pacific were less effective than elsewhere," Mr Negret said.

"The Pacific region of Colombia is extremely biodiverse and globally important with a high concentration of endemic species, so ensuring these protected areas work is especially important."

The team used forest cover information collected from satellites, with data covering 17 variables associated with deforestation, to compare both protected and non-protected areas that had similar environmental and social characteristics.

In total, the researchers analysed the effectiveness of 116 protected areas, which represent 9.8 per cent of the country's continental area.

UQ's Professor Martine Maron said the study showed how understanding the effectiveness of protected areas could be extremely useful in informing national and global conservation decisions.

"Protected areas can be less effective - either because they still experience deforestation or because they're placed in locations where no deforestation would have occurred even if they weren't protected," Professor Maron said.

"Evaluating the impact protected areas make to deforestation can help with determining whether to invest in improved management in existing protected areas or increase their coverage in strategic locations - or both.

"We hope that these insights can be taken into account in Colombia and around the globe.

"A similar approach can help any country or region effectively assess the performance of their protected areas at preventing ecosystem loss."

A new analysis of SARS-CoV-2, the virus that causes COVID-19, reveals that the pathogen can infect and replicate in cells that line the inside of the human intestines. The results show that the intestines are a target organ for the virus and could explain why some patients with COVID-19 experience gastrointestinal symptoms. As the COVID-19 pandemic continues to unfold across the world, scientists have prioritized understanding how exactly SARS-CoV-2 infects and damages human cells. Studies have shown that the virus enters epithelial cells in the lungs by exploiting an enzyme called ACE2, allowing the virus to replicate and spread further. The ensuing damage results in some of the respiratory symptoms that COVID-19 is known for, which can range from coughing and shortness of breath to pneumonia in more severe cases. Preliminary observations suggest that the virus may also infect cells in the gut: patients sometimes show gastrointestinal symptoms like diarrhea, and researchers know that gut epithelial cells also harbor ACE2. Mart Lamers and colleagues generated 3D structures that display all cell types of the human small intestinal epithelium and grew them in four different culture conditions. The human small intestinal organoids grown in different conditions expressed varying amounts of ACE2 and could be infected with SARS-CoV-2. Using electron microscopy, the authors discovered that the virus infected both mature and progenitor enterocytes, which are intestinal absorptive epithelial cells that line the inner surface of the intestines. They also found that the virus provoked the activity of genes involved with antiviral responses. Notably, the rates of infection were similar across the organoid models, indicating that even low quantities of ACE2 may be enough for the virus to infect epithelial cells. Lamers et al. suggest that human organoid models will offer a useful resource for researchers studying the basic biology of SARS-CoV-2 and other coronaviruses.

Researchers at EMBL's European Bioinformatics Institute (EMBL-EBI), the University of Dundee and the Wellcome Sanger Institute analysed over 2700 genomes from C. elegans worms in order to better understand the causes of mutations. Their findings, published today in Nature Communications, characterise how DNA mutations result from the combined action of DNA damage and inaccurate DNA repair mechanisms.

A cell's DNA is constantly exposed to physical and chemical stresses - or genotoxins - that can damage it and cause mutations. However, cells have a myriad of repair mechanisms to fix DNA lesions soon after they arise. Occasionally, the restorative repair process fails, either by making extra errors, or by failing to detect the DNA lesions altogether. This leads to mutations, which are the root cause of cancer.

Many genotoxins, like those found in tobacco smoke, were thought to cause a unique suite of mutations in the genome, recognisable as a mutational signature. "Detecting such signatures in cancer allows scientists to trace what caused the damage in the first place, and aid prognosis and treatment by pointing to certain vulnerabilities," explains Nadezda Volkova, recent PhD graduate at EMBL-EBI.

However, many mutational signatures observed in cancer genomes do not seem to relate to any single genotoxin and others appear to result from a combination of factors. To understand the origin of these signatures, Volkova and colleagues tested the effects of more than 150 combinations of twelve genotoxins on C. elegans worms whose DNA repair mechanisms were either unaltered or faulty. The scientists experimentally demonstrated that mutational signatures result from a combined action of DNA damage and specific repair mechanisms.

DNA repair and mutational signatures

"A lot of DNA alterations that we observed in our study occur in human cancer as well, but we found that mutational signatures are more variable than we previously thought," says Volkova.

The scientists found that different types of DNA alterations induced by the same genotoxin are often fixed by different DNA repair pathways, some error-free, others error-prone. As a result, a single genotoxin may leave a variety of mutational signatures at various rates, depending on the repair process.

While most DNA repair prevents mutations, it can also cause them. For example, Volkova and colleagues demonstrated that one particular mechanism, called translesion synthesis, is responsible for the majority of base mutations caused by genotoxin exposure as a trade-off for more severe and potentially more deleterious mutations. While many of these minor mutations may be harmless, in humans they can increase the probability of developing a tumour.

"In cancer genomics, there is an implicit expectation that for every signature, one could find a single cause: our analysis challenges that expectation. Behind each pattern, there are at least two unknowns: the damage that occurs and the repair capacity of the cell," says Moritz Gerstung, Group Leader at EMBL-EBI.

Bringing together cancer genomics and DNA repair

While the molecular mechanisms of DNA repair are very well-established, the exact types and frequency of mutations they can generate remained unclear until high-throughput sequencing entered the scene.

This study combines whole genome sequencing with an experimental screen to better understand the causes of mutational signatures. The results have potential implications for cancer research, diagnosis and treatment.

"Understanding the interplay between DNA damage and repair helps to better gauge the risk of cancer predisposition, and to understand the response to cancer treatment," says Bettina Meier, Senior Research Associate at the University of Dundee.

Mutational signatures have become a pillar of cancer genome analysis because they may shed light on the carcinogens cancer cells have been exposed to, and the repair mechanisms that were perturbed.

However, not all observed mutational signatures and their individual facets are fully understood. An experimental approach ensures that the observed patterns are the direct consequences of the conditions set by the scientists. It also helps understand how multiple DNA repair processes jointly shape mutational signatures.

"It took years to generate all these repair defective C. elegans, to systematically expose them to a panel of genotoxins, and to prepare, sequence and analyse their DNA. It is great to see that experimental work on C. elegans is directly relevant for interpreting cancer genomes," says Anton Gartner, Group Leader at the University of Dundee, recently appointed Associate Director of the IBS Center for Genomic Integrity at UNIST Ulsan, South Korea.

Scientists have called for labelling to warn the public about levels of arsenic in rice, after their research found half of rice varieties studied exceeded maximum limits on the deadly toxin.

In a study published in the journal Ecotoxicology and Environmental Safety (open access), a team at the University of Sheffield's Institute for Sustainable Food found 28 out of 55 rice samples sold in the UK contained levels of arsenic that exceeded European Commission regulations for rice meant for the consumption for infants or young children. The research is the first to measure differences in human health risks from arsenic using a substantial number of rice varieties marketed in the UK.

The results showed that brown rice contained higher levels of the carcinogen than white or wild rice because it contains the bran - the outer layer of the grain. Meanwhile, organically grown rice was found to contain significantly higher levels than non-organically grown rice. White rice contained the lowest levels of arsenic.

Considering the health implications, the researchers concluded that babies under the age of one must be restricted to a maximum of 20g per day of the 28 rice varieties that breached regulations, in order to avoid risks of developing cancer in later life. They have recommended that the UK government and European Commission introduce labelling to clarify whether rice is safe for consumption by babies and children under five.

Up to 90 per cent of UK households buy rice, with the average person consuming around 100g per week. Rice and rice-based products are widely used for weaning and as baby food, due to their nutritional benefits and relatively low allergic potential - but, according to the European Food Safety Authority, children are two-three times more susceptible to arsenic risks than adults due to their lower body weight.

Arsenic, which is classified as a Group 1 carcinogen by the International Agency for Research on Cancer, is water-soluble - so it accumulates in rice, which is grown in flooded fields more than other cereals. Arsenic exposure affects almost every organ in the body and can cause skin lesions, cancer, diabetes and lung diseases.

Dr Manoj Menon, Environmental Soil Scientist in the Department of Geography at the University of Sheffield and lead author of the study, said: "Brown and wild rice are healthy foods full of fibre and vitamins, and there is no need for grown-ups to avoid them - but it is concerning to see so many varieties sold in the UK breaching food safety regulations.

"Rice products are often considered a safe option for babies and young children, but our research suggests that for more than half of the rice we sampled, infants should be limited to just 20g per day to avoid risks associated with arsenic. The government and the European Commission must introduce labelling to warn people of arsenic levels in rice to enable families to make informed food choices."

The research was funded as part of the UK's Science and Technology Facilities Council (STFC) Food Network+. The network brings together more than 750 international and multidisciplinary researchers from across the agri-food sector to work with experts from STFC's research facilities, all with the aim of solving some of the world's greatest food sustainability challenges. Until April this year, the network was led by the University of Manchester. This is now being led by academics at the Institute for Sustainable Food.

The Institute for Sustainable Food at the University of Sheffield brings together multidisciplinary expertise and world-class research facilities to help achieve food security and protect the natural resources we all depend on.

CHICAGO (May 1, 2020): Stay-at-home orders caught many medical practices and health care systems off guard, leaving them ill-equipped to rapidly adopt an efficient telemedicine platform so they could keep providing time-sensitive care to non-COVID-19 patients. To help organizations rapidly introduce telemedicine as an alternative option, a urology group in North Carolina developed a guide that enabled them to convert all in-person visits to telemedicine in three days. They report their experience in an "article in press" appearing on the Journal of the American College of Surgeons website ahead of print.

The guide, which the authors call a toolkit, uses a common electronic medical record (EMR) system, Epic, and widely available video portals like Google Duo and Doximity, to overcome social distancing edicts. The toolkit relies on eight essential elements readily available in any medical organization new to telemedicine. "One of our motivations for preparing the toolkit was to make it instantly available to any type of organization, large or small, that has an electronic medical record system," said lead author Catherine Matthews, MD, FACS, FACOG, professor of urology and gynecology, Wake Forest Baptist Health, Winston-Salem, N.C.

The eight essential components to successful telemedicine adoption are: an existing EMR, a one-hour training session for providers and staff, patient education on accessing the portal, availability of hardware like smartphones and video-capable computers, integration of new billing and coding functions, information technology support, an audiovisual platform, and patient and caregiver buy-in.

"The first thing you have to figure out is which video platform is going to work most consistently," Dr. Matthews said. Through trial and error, she and her coauthors decided on pairing up the Epic EMR with the Doximity provider networking app. Patients can access the Doximity platform through a link sent in a text message, eliminating the need for them to download an additional app or log into an online portal.

The article acknowledges other options available for telemedicine: the MyChart video capability incorporated in the Epic EMR system, and even services such as FaceTime, Skype, WhatsApp, and Google Duo.

However, in reporting on their experience, the Wake Forest Baptist urology group found disadvantages to some of these alternatives. MyChart, for example, requires patients to sign up for the patient portal and download two separate apps. "It can take quite a bit of time for staff to educate patients about this option," Dr. Matthews said. "Patients not only have to have the device and Internet access; they have to have enough aptitude to complete those three separate steps." For providers using their personal devices, platforms like FaceTime and Skype disclose their personal cell phone or e-mail information. Doximity masks that personal contact information with the organization's office number.

Another key component is the ability to teach both staff and patients quickly how to use the technology. "After selecting the platform, engaging the office staff to be on board with virtual visits is the next most important step," said coauthor Whitney Smith, MD, a fellow in the female pelvic health service at Wake Forest Baptist Health. Staff training involved a one-hour session with a mock patient visit. The goal, she said, was to replicate all the key steps of the in-person visit in the virtual visit, from front desk check-in and nurse chart review to exam and checkout.

"Telemedicine is currently built as a physician platform," Dr. Matthews said. "We changed it to be inclusive of nurses; we engaged our nursing staff into the platform so that they continue to do the same roles that they do in person."

Days before the patient's telemedicine appointment, a nurse calls to notify the patient the visit is being changed from an in-office to telemedicine, and then walks the patient through the connection process. On the day of the visit, the nurse calls again 15 minutes before the visit to review the chart, "just like they would if the patient was there in the office," Dr. Matthews said.

About three and a half weeks into their telemedicine experience, the Wake Forest Baptist Health urology physicians see about 15 patient visits via telemedicine a day compared to 30 in-office visits, Dr. Smith added. Despite a lower total number of visits, Dr. Matthews noted that a high rate of new telemedicine patient visits convert to surgery scheduling. "Anecdotally, the efficiency from a surgical subspecialty perspective of the translation of new patient appointments to scheduling of future surgeries is currently 20 to 25 percent," she said. "So a surgeon who's not engaging in telemedicine is losing out on an opportunity to identify patients who will need surgery in the next two to three months."

There have been barriers to wider implementation of telemedicine. Reimbursement for telemedicine services had been one, but in March the Centers for Medicare and Medicaid Services issued a waiver that removed payment restrictions. Another barrier can be technology. Small percentages of people still don't have smartphones or home computers, and internet service can be limited, especially in some rural areas. Dr. Smith said that the group had concerns about some elderly patients not having access to technology. "However, they've been able to engage younger family members to help them with the technology, and actually we've had very good success with that," she said. For patients who don't have video capability, the CMS waiver accommodates voice-only visits.

Newcastle University researchers have developed a new class of self-forming membrane to separate carbon dioxide from a mixture of gases. Operating like a coffee filter, it lets harmless gases, such as nitrogen, exit into the atmosphere and then the carbon dioxide can be processed.

The team believe that the system may be applicable for use in carbon dioxide separation processes, either to protect the environment or in reaction engineering.

By growing the expensive part of the membrane - made from silver - during membrane operation, they dramatically reduced the demand for silver and the cost of the membrane.

The work is published in Energy and Environmental Science and Dr Greg Mutch, NUAcT Fellow from the School of Engineering, Newcastle University, UK explains, "We didn't build the entire membrane from silver, instead we added a small amount of silver and grew it within the membrane adding the functionality we desired.

"Most importantly, the performance of the membrane is at the level required to be competitive with existing carbon capture processes - in fact, it would likely reduce the size of the equipment required significantly and potentially lower operating costs."

What is carbon capture and why is it needed?

Carbon dioxide emissions are the main driver of climate change. Currently, our climate is approximately 1 °C warmer than pre-industrial times. We have already emitted enough carbon dioxide to warm the planet beyond 1.5 °C (there is a lag between emissions and warming), and we have international agreements in place to ensure that we do not pass 2 °C.

Warming beyond 2 °C will have disastrous consequences, including impacts on human health, food availability, large-scale migration and our environment. We urgently need new materials and processes that reduce the amount of carbon dioxide we emit to the atmosphere - these technologies are referred to as carbon capture and storage (CCS).

Although we are making big efforts with renewable energy and electric vehicles, the world is still predominantly powered by fossil fuels and we are very unlikely to be able to reduce that contribution in time to limit warming to less than 2 °C.

In addition, large modelling exercises such as by the Intergovernmental Panel on Climate Change, have repeatedly shown that the most cost-effective way to slow global warming always involves a significant amount of CCS (in the mix with e.g. renewable energy technologies).

The self-forming membrane

In a method never tried before, aluminium oxide supports in pellet and tubular form were used to grow the silver membrane. Silver was added to the membrane, and the conditions experienced during operation forced the silver to grow within the membrane, bestowing higher performance.

Using X-ray micro-computed tomography, the team were able to look inside the membrane and confirm that the permeation of CO2 and O2 stimulated self-assembly of silver dendrites.

Importantly, the performance of the membrane was shown through permeation measurements to be at the level required to be competitive with existing carbon capture processes. The permeability of the membrane was one order of magnitude higher than that required, and the flux of CO2 was the highest reported for this class of membrane.

Dr Mutch added: "These savings are important - the cost of carbon capture is one of the key factors limiting uptake of the technology. There is a common metric for membrane performance - the "upper bound". As our membrane relies on a unique transport mechanism, we avoid the limitations of most membrane materials and go far beyond the upper bound!

"We hope that this study inspires new ways to form membranes, that lower costs, as well as drives interest in this new class of membrane for future application to protect our environment."

Researchers at the UCLA Jonsson Comprehensive Cancer Center and colleagues have found that adding a drug once commonly used to treat schizophrenia to traditional radiation therapy helped improve overall survival in mice with glioblastoma, one of the deadliest and most difficult-to-treat brain tumors.

The findings, published in Proceedings of the National Academy of Sciences, show that a combination of radiation and the drug trifluoperazine not only targets glioblastoma cells but also helps overcome the resistance to treatment so common to this aggressive form of cancer. The results could prove promising for patients with the disease, for whom the median survival time is only 12 to 18 months following diagnosis.

Radiation is an integral part of therapy for people with cancer and one of the most effective treatments. In many cases, it can help cure the disease. But in glioblastoma, tumor cells often become resistant to radiation treatment because the radiation itself can induce "phenotype conversion," a process that turns certain non-tumor stem cells into tumor-producing cells, causing the cancer to reoccur.

"While radiotherapy is one of the few treatments that prolong survival in glioblastoma patients, radiation alone does very little in treating the disease in our models because we are dealing with highly aggressive tumors," said the study's senior author, Dr. Frank Pajonk, a professor of radiation oncology at the David Geffen School of Medicine at UCLA and a member of the Jonsson Cancer Center. "The drug trifluoperazine by itself does not do much either, but we found when you combine them, they become highly efficient. Importantly, the drug does not sensitize cells to radiation but rather prevents the occurrence of resistant glioma stem cells."

UCLA researchers have been exploring new ways to prevent glioblastoma tumor cells from becoming resistant to radiation by adding drugs to the treatment regimen that have traditionally been used for other purposes.

To find out if there were any existing drugs that could interfere with the radiation-induced phenotype conversion, the team screened more than 83,000 compounds through the shared resources at UCLA, which provides researchers access to specialized equipment and services to help them pursue cutting-edge research. They were able to identify nearly 300 compounds, including the dopamine receptor antagonist trifluoperazine, that had the potential to block phenotype conversion and improve the efficacy of radiation therapy.

Once trifluoperazine was identified, it was tested on mice with patient-derived orthotopic tumors. The team found that, when used in combination with radiation, trifluoperazine successfully delayed the growth of the tumors and significantly prolonged the overall survival of the animals.

Combining radiation treatment with trifluoperazine extended survival in 100% of the mice to more than 200 days, compared to 67.7 days in the control group receiving only radiation.

"Many preclinical glioblastoma studies report fairly small increases in overall survival in mice, and that rarely translates into benefits for patients," said Pajonk, who is also a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. "But here we see pretty drastic effects in improved overall survival, and I find that very encouraging. It gives us hope that this is all going to translate into a benefit for people."

The team plans to start a clinical trial this summer for people with recurrent glioblastoma to test using dopamine receptor antagonist with radiation therapy.

"I think we can find a combination of treatments with radiation that is very tolerable to patients and can do well," said co-author Leia Nghiemphu, an associate professor of clinical neurology at the Geffen School of Medicine and principal investigator on the upcoming clinical trial. "The next step is to see if we can stop this resistance to radiation in humans."

Despite concerns expressed by some experts, common high blood pressure drugs did not increase the risk of contracting COVID-19 - or of developing severe disease - in a study of 12,594 patients.

Published online May 1 in the New England Journal of Medicine, the study was launched in response to a March 17 joint statement issued by the American Heart Association, the American College of Cardiology, and the Heart Failure Society of America. It urgently called for research to answer a question raised by past studies: do high blood pressure (antihypertensive) drugs worsen COVID-19 patient outcomes?

Led by researchers from NYU Grossman School of Medicine, the study found no links between treatment with four drug classes - angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta blockers, or calcium channel blockers -- and increased likelihood of a positive test for COVID-19.

Further, the study found no substantial increase in risk for more severe illness (intensive care, use of a ventilator, or death) with any of the treatments in patients with the pandemic virus.

"With nearly half of American adults having high blood pressure, and heart disease patients more vulnerable to COVID-19, understanding the relationship between these commonly used medications and COVID-19 was a critical public health concern," says lead investigator Harmony Reynolds, MD, associate director of the Cardiovascular Clinical Research Center at NYU Langone Health. "Our findings should reassure the medical community and patients about the continued use of these commonly prescribed medications, which prevent potentially severe heart events in their own right."

For the study, the researchers identified patients in the NYU Langone Health electronic health record with COVID-19 test results. For each identified patient with COVID-19 test results, the team discretely extracted medical history needed for the analysis, which compared treated and untreated patients.

"Before our study, there were no experimental or clinical data demonstrating the consequences of using these medications one way or the other in people at risk for COVID-19," says senior study author Judith Hochman, MD, the Harold Snyder Family Professor of Medicine and Senior Associate Dean for Clinical Sciences at NYU Langone Health. "In terms of next steps, our plan is to use similar approaches to investigate other medications and their relationship to COVID-19 illness."

Cause for Concern

The study revolves around drugs that act on the renin-angiotensin-aldosterone hormonal system, which influences blood pressure. Central to this system is the signaling protein angiotensin II, levels of which are controlled by angiotensin-converting enzyme (ACE), say the authors. Angiotensin II narrows blood vessels to increase blood pressure, and the study drugs counter that, either by blocking ACE-induced increases in angiotensin II, or the ability of ACE to interact with its receptor signaling partners on cells.

According to the researchers, one version of ACE, angiotensin converting enzyme 2 (ACE2), is present in the outer membrane of lung cells. SARS-CoV-2, the current pandemic virus, has been shown to connect to ACE2 on lung cells, a first step toward viral infection. This led to concern in the field that ACE inhibitors and ARBs might increase or worsen COVID-19 infection. Past studies in animal models had suggested that ACE inhibitors and ARBs increase ACE2 production in other organs, but how they related to ACE2 levels in the lungs was not known.

On the other hand, ACE inhibitors and ARBs had been shown elsewhere to reduce lung injury in certain viral pneumonias, creating speculation that they might be helpful. The new study was designed to address these contradictions.

ANNAPOLIS, Md. - Many have claimed the Justinianic Plague (c. 541-750 CE) killed half of the population of Roman Empire. Now, historical research and mathematical modeling challenge the death rate and severity of this first plague pandemic.

Researchers Lauren White, PhD and Lee Mordechai, PhD, of the University of Maryland's National Socio-Environmental Synthesis Center (SESYNC), examined the impacts of the Justinianic Plague with mathematical modeling. Using modern plague research as their basis, the two developed novel mathematical models to re-examine primary sources from the time of the Justinianic Plague outbreak. From the modeling, they found that it was unlikely that any transmission route of the plague would have had both the mortality rate and duration described in the primary sources. Their findings appear in a paper titled "Modeling the Justinianic Plague: Comparing hypothesized transmission routes" in PLOS ONE.

"This is the first time, to our knowledge, that a robust mathematical modeling approach has been used to investigate the Justinianic Plague," said lead author Lauren White, PhD, a quantitative disease ecologist and postdoctoral fellow at SESYNC. "Given that there is very little quantitative information in the primary sources for the Justinianic Plague, this was an exciting opportunity to think creatively about how we could combine present-day knowledge of plague's etiology with descriptions from the historical texts."

White and Mordechai focused their efforts on the city of Constantinople, capital of the Roman Empire, which had a comparatively well-described outbreak in 542 CE. Some primary sources claim plague killed up to 300,000 people in the city, which had a population of some 500,000 people at the time. Other sources suggest the plague killed half the empire's population. Until recently, many scholars accepted this image of mass death. By comparing bubonic, pneumonic, and combined transmission routes, the authors showed that no single transmission route precisely mimicked the outbreak dynamics described in these primary sources.

Existing literature often assumes that the Justinianic Plague affected all areas of the Mediterranean in the same way. The new findings from this paper suggest that given the variation in ecological and social patterns across the region (e.g., climate, population density), it is unlikely that a plague outbreak would have impacted all corners of the diverse empire equally.

"Our results strongly suggest that the effects of the Justinianic Plague varied considerably between different urban areas in late antiquity," said co-author Lee Mordechai, an environmental historian and a postdoctoral fellow at SESYNC when he wrote the paper. He is now a senior lecturer at the Hebrew University of Jerusalem, and co-lead of Princeton's Climate Change and History Research Initiative (CCHRI). He said, "This paper is part of a series of publications in recent years that casts doubt on the traditional interpretation of plague using new methodologies. It's an exciting time to do this kind of interdisciplinary research!"

Using an approach called global sensitivity analysis, White and Mordechai were able to explore the importance of any given model parameter in dictating simulated disease outcomes. They found that several understudied parameters are also very important in determining model results. White explained, "One example was the transmission rate from fleas to humans. Although the analysis described this as an important parameter, there hasn't been enough research to validate a plausible range for that parameter."

These high importance variables with minimal information also point to future directions for empirical data collection. "Working with mathematical models of disease was an insightful process for me as a historian," reflected Mordechai. "It allowed us to examine traditional historical arguments with a powerful new lens."

Together, with other recent work from Mordechai, this study is another call to examine the primary sources and narratives surrounding the Justinianic Plague more critically.

An international team of astronomers has captured fifteen images of the inner rims of planet-forming disks located hundreds of light years away. These disks of dust and gas, similar in shape to a music record, form around young stars. The images shed new light on how planetary systems are formed. They were published in the journal Astronomy & Astrophysics.

To understand how planetary systems, including our own, take shape, you have to study their origins. Planet-forming or protoplanetary disks are formed in unison with the star they surround. The dust grains in the disks can grow into larger bodies, which eventually leads to the formation of planets. Rocky planets like the Earth are believed to form in the inner regions of protoplanetary disks, less than five astronomical units (five times the Earth-Sun distance) from the star around which the disk has formed.

Before this new study, several pictures of these disks had been taken with the largest single-mirror telescopes, but these cannot capture their finest details. "In these pictures, the regions close to the star, where rocky planets form, are covered by only few pixels," says lead author Jacques Kluska from KU Leuven in Belgium. "We needed to visualize these details to be able to identify patterns that might betray planet formation and to characterize the properties of the disks." This required a completely different observation technique. "I'm thrilled that we now for the first time have fifteen of these images," Kluska continued.

Image reconstruction

Kluska and his colleagues created the images at the European Southern Observatory (ESO) in Chile by using a technique called infrared interferometry. Using ESO's PIONIER instrument, they combined the light collected by four telescopes at the Very Large Telescope observatory to capture the disks in detail. However, this technique does not deliver an image of the observed source. The details of the disks needed to be recovered with a mathematical reconstruction technique. This technique is similar to how the first image of a black hole was captured. "We had to remove the light of the star, as it hindered the level of detail we could see in the disks", Kluska explains.

"Distinguishing details at the scale of the orbits of rocky planets like Earth or Jupiter (as you can see in the images) -- a fraction of the Earth-Sun distance -- is equivalent to being able to see a human on the Moon, or to distinguish a hair at a 10 km distance," notes Jean-Philippe Berger of the Université Grenoble-Alpes, who as principal investigator was in charge of the work with the PIONIER instrument. "Infrared interferometry is becoming routinely used to uncover the tiniest details of astronomical objects. Combining this technique with advanced mathematics finally allows us to turn the results of these observations into images."

Irregularities

Some findings immediately stand out from the images. "You can see that some spots are brighter or less bright, like in the images above: this hints at processes that can lead to planet formation. For example: there could be instabilities in the disk that can lead to vortices where the disk accumulates grains of space dust that can grow and evolve into a planet."

The team will do additional research to identify what might lie behind these irregularities. Kluska will also do new observations to get even more detail and to directly witness planet formation in the regions within the disks that lie close to the star. Additionally, Kluska is heading a team that has started to study 11 disks around other, older types of stars also surrounded by disks of dust, since it is thought these might also sprout planets.

Bethesda, MD (April 30, 2020) -- Transferring fecal matter from the digestive systems of healthy donors to extremely ill patients who had previously been infected with drug-resistant bacteria resulted in shorter hospital stays, fewer bloodstream infections and infections that were easier to treat, according to research that was selected for presentation at Digestive Disease Week® (DDW) 2020. DDW® data will be published in the May online supplements to Gastroenterology and GIE: Gastrointestinal Endoscopy.

The study's researchers conducted the transfer, known as fecal microbial transplantation or FMT, in 20 patients infected during extensive medical care with multi-drug resistant organisms, including carbapenemase-producing Enterobacteriaceae (such as Escherichia coli), vancomycin-resistant enterococci or extended-spectrum beta-lactamase Enterobacteriaceae. Patients were followed for six months after the transplantation and their clinical course compared with six months prior to FMT.

While the resistant bacteria were cleared in only 41 percent of the 17 patients who completed the full follow-up, researchers found other benefits to the patients, who had been repeatedly hospitalized and treated for a variety of severe conditions. The sample included hematological cancer patients in need of stem-cell transplants and kidney transplant patients with urinary and bloodstream infections with bacteria that were multi-drug resistant.

"Many of these patients have had recurrent, prolonged courses of heavy-duty antibiotics, end-of-the-line treatments with high toxicity profiles, and repeated hospital stays. They had given up work or had family members forced to give up work to care for them -- having a huge impact on quality of life," said Benjamin Mullish, MD, a lead researcher and clinical lecturer in the Division of Digestive Diseases, Imperial College London, England. "After this experimental treatment, we saw many in this group being able to go back to work, play with their grandkids and have an overall much better quality of life."

Previous research has found that FMT is effective in treating C. difficile, a difficult-to-treat health care-associated infection that often causes severe diarrhea in hospitalized patients. For this study, researchers wanted to know whether FMT could help decolonize, or remove from the patients' bodies, multi-drug resistant bacteria that have developed resistance to more than one type of antibiotic. Multi-drug resistant organisms require broader-acting last-resort treatments that can have severe side-effects. Researchers also wanted to know if FMT could impact other clinical outcomes like length of hospital stay, readmissions and development of bloodstream infections.

Across all patients, there was a reduction in bloodstream infections with resistant organisms and total bloodstream infections. Eight patients improved to a point where they were able to undergo stem-cell transplants within six months after FMT. No serious adverse events related to FMT were reported.

The results suggest that the benefits of FMT may not be only from decolonizing resistant organisms, but there may be positive impacts from other microbiota-related mechanisms that require additional study.

A limitation of the study is that instead of a using a control group, researchers compared patients' conditions before and after treatment, but results were dramatic enough in these very sick patients to warrant additional research.