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SASKATOON - An innovative radiation treatment that could one day be a valuable addition to conventional radiation therapy for inoperable brain and spinal tumors is a step closer, thanks to new research led by University of Saskatchewan (USask) researchers at the Canadian Light Source (CLS).

Microbeam radiation therapy (MRT) uses very high dose, synchrotron-generated X-ray beams--narrower than a human hair--to blast tumours with radiation while sparing healthy tissue. The idea is that MRT would deliver an additional dose of radiation to a tumor after maximum conventional radiation therapy has been tried, thereby providing patients with another treatment that could extend their lives.

But the longstanding questions have been: What is the optimal X-ray energy range of the MRT radiation dose that will both penetrate the thickness of the human body and still spare the healthy cells? How can the extremely high radiation doses be delivered and measured with the accuracy necessary for human treatment?

In a just-published paper in Physics in Medicine and Biology, the research team is the first to show that MRT can be scaled up for human radiation treatment. The team has identified how the radiation can be optimally delivered to ensure the safety and effectiveness of the potential human cancer treatment.

"The challenge has been to determine the ideal energy range needed so that the therapy can be used in humans with the next generation of synchrotrons," said Farley Chicilo, a USask PhD student in bio-medical engineering and lead author of the paper.

The energy range that's available now at synchrotrons around the world is not sufficient to penetrate the thickness of the human body.

"We were able to identify the higher X-ray energy range needed to penetrate the thickness of the human body, validating predictions from mathematical modeling," said Chicilo, noting that mathematical modeling had indicated the optimal X-ray energy would be 150 to 250 kiloelectron volts (keV).

MRT has a key advantage over other types of radiation: because the microscopically narrow beam of bombarding X-rays is sectioned like the teeth on a comb, the unirradiated healthy tissue in the spaces between the fine microbeams is able to help heal the irradiated tissue in the microbeam path.

"For MRT to be successful, we need the parallel microbeams to be as sharply defined as possible," Chicilo said. "Imagine a tumour therapy using knife cuts so thin that they could cut completely through an animal's spinal cord, and not paralyze the animal. MRT is that thin knife cut."

The team's experiment showed that at 150 keV, the high-energy, high-intensity microbeams were not blurred, allowing the damaged cells in the microbeam path to be quickly repaired by adjacent healthy cells.

"One might think that at higher energy the electrons would scatter more and damage surrounding tissue but it's the opposite," said USask medical imaging expert Dean Chapman, Chicilo's co-supervisor. "This new knowledge will affect how dedicated machines for MRT will be developed in future."

Another significant challenge for scientists investigating MRT has been the lack of a detector that can accurately and precisely measure the extremely high radiation doses at micron scale resolution.

"What our team did was to develop a unique high-dose radiation measurement detector technique and use it to determine the exact radiation dose contour delivered by the microbeam," said USask engineering professor Safa Kasap, who has been working on X-ray imaging detectors for more than two decades and is Chicilo's supervisor.

The detector uses a special glass containing samarium, a rare Earth ion, that helped the team measure the radiation dose and ensure it is precise and controlled. The glass itself was prepared by Andy Edgar at the Victoria University of Wellington in New Zealand, a long-time collaborator of the USask group. The detector using this glass and the measurement apparatus were designed and developed at USask, the only place that uses this unique material for MRT measurement of ionizing radiation.

Samarium glows orange when excited by a blue laser, but when exposed to X-rays, the ions gain an electron and glow red. By observing the ratio of orange to red light, the team was able to measure the dose deposited at a very high resolution over the large dose range of MRT.

"This is one of the best detectors that has been developed for measuring the detailed contour of the edges of the microbeam," said Kasap.

The new-found ability to predict both an ideal energy range of X-rays and the ideal width of the microbeams for human therapy will be "critical in future for treatment planning in clinical trials," said USask adjunct professor and team member Dr. Fred Geisler, a nuclear physicist and neurosurgeon who is an internationally renowned expert in spinal cord injury and spinal surgery.

"These are important and exciting steps in a process to make MRT available for human cancer treatment," Geisler said, adding this could take a decade.

Synchrotrons are the only means of generating high enough strength of parallel X-rays for MRT research. The CLS is one of only a few facilities in the world that can produce microbeams with the appropriate energy range for testing biological and medical applications.

Having the CLS located on the USask campus along with the Western College of Veterinary Medicine and the Saskatchewan Cancer Agency (SCA) creates a critical mass of multi-disciplinary researchers to continue to advance MRT.

In fact, Chicilo and some of his co-authors are currently working with the SCA on a mouse model to determine when to perform MRT after standard radiation therapy has already been tried.

Air pollution in China has received great attention due to its effects on climate and human health. A recent study showed the contrasting variation of air pollutants in China using long-term comprehensive data sets from 2013 to 2017, during which Chinese government took major efforts to reduce anthropogenic emission in polluted regions. A significant decreasing trend in the PM2.5 concentration in heavily polluted regions of the eastern China was happening. As a consequence, the heavily polluted days decreased in corresponded regions. However, surface ozone showed increasing trends in most of the cities from 2013 to 2017, which indicates a stronger photochemical pollution. 'It is so inspiring that the blue sky is coming back. However, surface ozone is increasing, which is a new challenge for future air pollution control. For the scientists, I think it is a unique opportunity to advance our current atmospheric chemistry and physics knowledge about influence of anthropogenic activity on our atmosphere' says Yonghong, the first author of the work.

In addition, using long-time measurements of aerosol chemical composition in urban Beijing, they revealed that concentrations of organic aerosol, nitrate, sulfate, ammonium and chloride showed a remarkable reductions from 2013 to 2017, connecting the decreases in aerosol precursors with corresponding chemical components closely.

New imaging technology allows scientists to see the widespread loss of brain synapses in early stages of Alzheimer's disease, a finding that one day may help aid in drug development, according to a new Yale University study.

The research, published May 13 in Alzheimer's & Dementia: The Journal of the Alzheimer's Association, compared the density of synapses, which transmit signals between neighboring brain cells, in people with early stages of Alzheimer's with those of people who have no evidence of the disease. As expected, the loss of synapses in those with an early stage of Alzheimer's was particularly high in areas surrounding the hippocampus, an area of the brain crucial to formation of memory, the scientists report.

"However, our new methods enable us to detect widespread synaptic losses thoughout the brain," said Yale's Adam Mecca, assistant professor of psychiatry and first author of the paper. "This gives us confidence that we may use these results as a biomarker outcome for therapeutic trials, which could help speed development of new drugs to combat the disease."

To get a clearer picture of the early effects of Alzheimer's, the researchers used positron emission tomography (PET) imaging of a protein found in almost all brain synapses. Previous imaging technologies had been able to show in broad strokes the loss of brain tissue or reduced brain metabolism in Alzheimer's. However, the new PET scans show the distribution of synaptic damage, a more specific disease pathology present at early stages of the disease, the authors say.

"These methods will allow us to examine synaptic loss at still earlier stages of disease -- when people have evidence of Alzheimer's pathogenesis but have not yet manifested symptoms," said Christopher van Dyck, professor of psychiatry, neurology, and neuroscience, and senior author of the study.

The Yale team recently received a grant to conduct more synaptic imaging and relate synaptic loss to other disease markers for Alzheimer's, including amyloid and tau accumulation.

COVID-19, the disease caused by coronavirus SARS-Cov-2, has infected over 4 million people in 212 countries, of whom at least 272,000 have died. The ongoing economic and social impact of the pandemic is staggering, but despite a daily flood of news on the disease, few laypeople know that paradoxically, COVID-19 mostly kills through an overreaction of the immune system, whose function is precisely to fight infections.

In a new review article - explicitly targeted to non-specialists as well - in Frontiers in Public Health, a team of experts from Zunyi Medical University review the epidemiology, disease pathway, symptoms, diagnosis, and current treatment of severe COVID-19. They stress the key role of a potentially lethal overreaction of the immune system in the progression of the disease.

They explain step-by-step what is known about how the virus infects the airways, multiplies inside cells, and in severe cases causes the immune defenses to overshoot with a "cytokine storm". This storm is an over-activation of white blood cells, which release too-great amounts of cytokines - inflammation-stimulating molecules - into the blood.

"Similar to what happens after infection with SARS and MERS, data show that patients with severe COVID-19 may have a cytokine storm syndrome. The rapidly increased cytokines attract an excess of immune cells such as lymphocytes and neutrophils, resulting in an infiltration of these cells into lung tissue and thus cause lung injury," explains author Professor Daishun Liu from Zunyi Medical University, China.

The cytokine storm ultimately causes high fever, excessive leakiness of blood vessels, blood clotting inside the body, extremely low blood pressure, lack of oxygen and excess acidity of the blood, and build-up of fluids in the lungs ("pleural effusion").

White blood cells are misdirected to attack and inflame even healthy tissue, leading to failure of the lungs, heart, liver, intestines, kidneys, and genitals (Multiple Organ Dysfunction Syndrome, MODS). This may worsen and shutdown the lungs (Acute Respiratory Distress Syndrome, ARDS) due to the formation of a so-called hyaline membrane, composed of debris of proteins and dead cells, lining the lungs, which makes absorption of oxygen difficult. Most deaths due to COVID-19 are therefore due to respiratory failure.

Liu et al. explain how in the absence of a specific antiviral cure for COVID-19, the goal of treatment must be to the fight the symptoms, lowering the mortality rate through intensive maintenance of organ function, for example an artificial liver blood purification system or renal replacement therapy to filtrate the blood through mechanical means.

Especially important are methods to supplement or replace lung function, for example through non-invasive mechanical ventilation through a mask, ventilation through a tube into the windpipe (if possible with the refinement of Positive End Expiratory Pressure, PEEP, where the ventilator delivers extra pressure at the end of each breath of keep the lung vesicles open throughout), the administration of heated and humidified oxygen via a tube in the nose ("transnasal high-flow oxygen"), or a heart-lung bypass.

The authors conclude by stressing the importance of preventing secondary infections: SARS-Cov-2 also invades the intestines, where it causes inflammation and leakiness of the gut lining, allowing the opportunistic entry of other disease-causing microorganisms. They advocate that this should be prevented with nutritional support, for example with probiotics - beneficial bacteria that protect against the establishment of harmful ones - and nutrients and amino acids to improve the immune defenses and function of the intestine.

"Because treatment for now relies on aggressive treatment of symptoms, preventative protection against secondary infections, such as bacteria and fungi, is particularly important to support organ function, especially in the heart, kidneys, and liver, to try and avoid further deterioration of their condition," concludes Liu.

Blockchain, the technology that underpins digital currency and has acquired a slightly tainted reputation as a useful tool for organised crime, is coming out of the shadows and is set to become a friend to consumers, protecting them from tainted food, fake medicine, fraud and products with illegal or unethical origins, a new study from the University of Bath shows.

"Blockchain technologies are likely to form part of supply chain solutions in the same way that bar and QR codes and RFID tags are now mainstream. But blockchain offers much more in terms of product visibility and traceability, helping consumer safety and allowing the public to make more informed choices about what, how and where they buy from," Michael Rogerson, researcher at the University's School of Management, said.

Rogerson's research and case studies showed blockchain - essentially a system that creates a list or record of actions that is very difficult to change - can bring particular advantages to the food industry, not only in terms of ensuring food quality but also in giving visibility into how the food was produced, and its environmental footprint.

"Recent years have seen a spate of environmental, social, and health scandals as well as persistent abuses and fraud. Consumers are increasingly paying attention to the impact food production has on the environment and on the people working in the supply chain. Cases of modern slavery have been discovered in Vietnamese fisheries, and child labour in cocoa supply chains shows no sign of abating," Rogerson said.

"Perhaps the best known fraud was the 2013 horsemeat scandal in the UK, where up to 60% of products labelled as beef were in fact horse. There have also been instances of infected chicken being sold in UK supermarkets and a long-standing issue in the United States of Romain lettuce causing E.coli poisoning has only recently ended," he added.

Existing technologies allow firms and consumers to know where products have been and when, or their nutritional value and allergens, but they do not offer any information about what actually happens at each point in the supply chain - something blockchain can remedy if deployed correctly. This can give companies a competitive advantage by offering data and reassurance about the provenance of goods, Rogerson said.

Larger companies have begun to recognize that potential but have been reticent about sharing the outcomes of their trials with blockchain, which means industry has been slow to share and learn, delaying advances in food safety and denying potential benefits to consumers, Rogerson said. He found smaller organizations were more willing to share their experience for his research - "Blockchain:case studies in food supply chain visibility".

The research paper studied several cases, including a Shanghai-based company Techrock, which has developed a package that can assure parents that a particular baby formula is safe. A string of Chinese infant formula scandals beginning in 2008 killed at least 18 babies, affected 300,000, and destroyed confidence in a product many parents relied upon to feed their children.

Parents can scan the product with a mobile phone and instantly see data on the baby formula's production, logistics and a picture of what it should look like - crucial for combatting fake products. They can also see if the product has been opened and resealed.

In Australia, an agricultural commodity management platform Agridigital provides consumers with data that enables them to verify a marketing claim. Their system digitally captures inputs from farmers, data from supply processes and uses RFID tags to monitor product movements. Data is stored on a Quorum blockchain. They match the data against operational best practices to show conformance, which consumers can view using a mobile app.

And in Fiji the World Wildlife Fund has partnered with blockchain provider TraSeable to protect the sustainability of fisheries. The partnership collects data on fishing grounds, location and route, catch logs, and crew details using smartphones and stores it on a public Ethereum blockchain. Once fish are unloaded, QR-tagging is used to track fish to stores, where consumers can access these data using a mobile app.

"These positive uses and developments bode well for the future of blockchain although it is important to note that there has been much hype, and much myth, surrounding its potential. With this research we hope to show industry what is actually possible and give a realistic appraisal of the limitations of this safety-enhancing technology," Rogerson said.

Rogerson said it was important to understand the limitations around the technology and have an honest discussion about the issues to be resolved. In particular, to reduce fraud or error supply chains need to be digitized from origin to end user. And while the technology can improve visibility of what happens to a product at each point in the supply chain, that visibility will still rely on humans putting in the correct information, he said.

Additionally there are currently a variety of blockchain systems in use in supply chains but no agreed standards which could cause interoperability problems with data, particularly when it comes to consumers reading them on a variety of smartphone types and apps. And the cost of implementing such systems may restrict their use to higher value food products, medicines or goods where consumers are prepared to pay a premium, such as for baby formula.

"But possibly the largest obstacle might be the reputational issues attached to blockchain and the negative media coverage of cryptocurrencies. It would appear that blockchain, which the Economist once called 'the trust machine', has a trust issue and companies will have to work hard to overcome that - but our research shows that this work will pay off," Rogerson said.

To some, farming might seem simple: plant seeds, help them grow, then sell the product. But the reality is much different. Farming requires many complex decisions throughout the year.

One such decision is seeding rate - the number of seeds planted per acre. The best seeding rate for soybean fields is one of the most debated topics for those involved in agriculture.

Researchers have long tried to help farmers find a clear answer. A recent study by soybean scientists at Corteva Agriscience and universities across the U.S. might provide the most complete answer yet. They set out to determine what is called the optimal seeding rate for soybean growers.

"The optimal soybean seeding rate is a commonly discussed topic with many opinions, based on individual experience and regional experiments," says Adam Gaspar of Corteva Agriscience. "Our study is the largest soybean seeding rate study ever conducted. We hope to provide help to soybean growers based on where they are farming to help reduce risk and optimize yield potential."

A farmer could plant too little seed and not get maximum production. Or, they could plant too much and not make up the extra money spent. Optimum seeding rate is the ideal amount of seed to use to maximize production and minimize risk.

"Farm margins are very tight," Gaspar explains. "Growers are looking for ways to most efficiently use resources and control associated expenses, while not unnecessarily increasing their risk. Their seed purchase is a large investment, and one that has big implications. If they don't get it right, they are putting profitable returns at risk."

This collaborative research project is the first to determine seeding rates in different environments with low, medium, or high productivity. Medium productivity is average yield with low and high being below or above average. The productivity is influenced by various factors like soil type, topography and climate.

Researchers gathered data on the effects of seeding rate on soybean yield in 12 states plus Ontario, Canada from 2005 to 2007 and 2012 through 2017. The seeding rates, productivity and yield were analyzed.

Overall, the results showed that farmers should increase seeding rates in areas of lower productivity and reduce them in areas of higher productivity. As farmers know, these areas may vary in different parts of the farm. The productivity can even vary within different areas of each field.

Farmers can use this information to guide their decisions regarding how many seeds to plant per acre to maximize yield. Their seeding rate decisions may change from field to field, based on soil type, topography and previous yields. The seeding rate can even be changed within each field using variable rate planter technology.

"These findings will ultimately help growers use the optimal seeding rate between and within each field to optimize production, while limiting their risk of adverse yields due to seeding rates that are too high or too low," Gaspar says. "Also, it will emphasize the importance of establishing and maintaining an adequate plant stand until harvest. This is especially true in fields or areas of a field with low to medium productivity."

The work is unique because it brings together so many public and private researchers to share knowledge and resources. This directly helps soybean growers across North America.

"The annual seed purchase is one of the farmers' larger costs," says Gaspar. "It is critical for their success to make sure their seeding rate maximizes production and limits their downside risk. Our work will help soybean farmers manage their seed investment by being able to accurately adjust their seeding rates."

Researchers at Orygen and La Trobe University in Melbourne, Australia have completed a rapid review of contemporary epidemic and pandemic research to assess the potential impact of COVID-19 on people with psychosis.

The review, published online ahead of print in Schizophrenia Research, found an increase in the prevalence of psychosis as a result of COVID-19 would likely be associated with viral exposure, pre-existing vulnerability and psychosocial stress. The review also suggested that people with psychosis may present a major challenge and potential infection control risk to clinical teams working with them.

Orygen research fellow and co-lead author on the study, Dr Ellie Brown looked at published research on viruses such as MERS, SARS, swine influenza and other influenzas that have occurred in the past 20 years, to examine if there was any connection to how these viruses might impact people with psychosis.

"COVID-19 is a very stressful experience for everyone, particularly those with complex mental health needs," Dr Brown said. "We know that psychosis, and first episodes of psychosis, are commonly triggered by substantial psychosocial stresses. In the context of COVID-19, this could include stress relating to isolation and having to potentially remain within challenging family situations.

"People with psychosis are a population that are particularly vulnerable in the current COVID-19 pandemic and their needs are often overlooked.

"This research shows that their thoughts around contamination, and their understanding around concepts such as physical distancing may be different from the wider population."

Co-lead author of the research, Professor Richard Gray of La Trobe University said another important finding from the research was that psychotic symptoms, such as hearing voices, may occur in a small number of people with COVID-19.

"Maintaining infection control procedures when people are psychotic is challenging," Professor Gray said. "In order for them not to become potential transmitters of the virus, clinicians and service providers may benefit from specific infection control advice to mitigate any transmission risk."

Dr Brown said that although mental health disorders such as depression and anxiety were important to focus on during the COVID-19 pandemic, the community needed to be aware that the smaller but more severe spectrum of mental health conditions could be impacted as well.

Professor Gray agreed. "This is a group that's probably going to need more support, with isolation, physical distancing, hand washing etc, and clinicians may be the ones who need to be thinking and working on this to assist this vulnerable population," he said.

A group of tiny RNA that should attack the virus causing COVID-19 when it tries to infect the body are diminished with age and chronic health problems, a decrease that likely helps explain why older individuals and those with preexisting medical conditions are vulnerable populations, investigators report.

MicroRNAs play a big role in our body in controlling gene expression, and also are a front line when viruses invade, latching onto and cutting the RNA, the genetic material of the virus, says Dr. Sadanand Fulzele, aging researcher in the Department of Medicine and Center for Healthy Aging at the Medical College of Georgia at Augusta University.

But with age and some chronic medical conditions, the attacking microRNA numbers dwindle, reducing our ability to respond to viruses, says Dr. Carlos M. Isales, co-director of the MCG Center for Healthy Aging and chief of the MCG Division of Endocrinology, Diabetes and Metabolism.

Much like not having enough troops on the ground in an actual war, the coronavirus is then better able to do what it does naturally, which is hijack our cell machinery so it can replicate, say the researchers who report in the journal Aging and Disease what appear to be key microRNA involved in responding to this virus. They have a longer-term goal of identifying the biggest hitters and replenishing those troops.

They looked at the RNA sequence of actually two coronaviruses, SARS, which surfaced in 2002, and SARS-CoV-2, which causes COVID-19, and the sequence of the microRNAs that appeared to be attacking the virus, then used computer simulation to figure out which would logically fit together like puzzle pieces. Their perusal included four samples of SARS and 29 samples of SARS-CoV-2, taken between January and April 2020 from five continents covering 17 countries from the United States to Germany to Thailand.

They found 848 microRNAs that target the SARS genome and 873 microRNAs that target SARS-CoV-2 genome. They found 558 of the microRNAs fighting SARS also present in SARS-CoV-2, while 315 microRNAs were unique to SARS-CoV-2, and 290 were unique to SARS. MicroRNAs most proficient at attacking SARS-CoV-2 showed more than 10 target sites and might ultimately be found to be the most proficient at fighting the virus, which, in a few months, has changed much of the way the world functions.

They also found the microRNAs targeting SARS-CoV-2 were associated with more than 72 biological processes -- from the production of molecules to the immune response -- and that many are known to become dysregulated and/or diminish in number with age and with underlying medical conditions like diabetes and cardiovascular disease, a likely factor in the increased disease presentation and death rates seen in these individuals, the investigators say.

An example is microRNAs like miR-15b-5p, which has a high affinity for SARS-CoV-2, but is downregulated in coronary artery disease, says corresponding author Fulzele. In healthy, younger people, these microRNAs whose nature is to bind to the virus, are more apt to do as they should and prevent replication, he adds.

In the 29 worldwide samples of SARS-CoV-2, 19 had identical microRNAs, which indicates the virus has a fairly uniform presence internationally and that any effective treatments or vaccines should have broad impact, Isales says.

Next steps include studies in culture and lab animals to ensure findings are consistent with the computer analysis of human microRNAs in this study.

"The most important and striking feature of COVID-19 is the increased case fatality rate in aged individuals," the investigators write, with the CDC reporting that nearly half of patients requiring hospitalization are age 65 and older, and these more senior individuals account for about 80% of the deaths. Fulzele, Isales and their colleagues wanted to know more about why.

"My perspective is there is a key set of microRNAs that are important in triggering this abnormal response, in making older patients more susceptible," says senior author Isales. "We are looking at microRNAs in general dropping, but there is a specific subset that is key. The question is whether we can we target those as a therapy."

Cocktails of multiple key microRNA, potentially given through the nose, might help restore sufficient levels of the key virus fighters, the investigators say.

They already are moving toward producing synthetic microRNA that could supplement this frontline weakened by age or disease, Fulzele says. Future studies also include pinning down which microRNA would be most impactful as an adjunct therapy, for example with the drug remdesivir, under study now for COVID-19, which works to stop the virus' pirating of healthy cell machinery.

Another question to pursue is whether some younger people, who also are seriously sickened by SARS-CoV-2 infection, already don't make sufficient numbers of some of the key protective microRNA, Isales says.

The microRNA present in the cells of our body typically target both the 3'-UTR (three prime untranslated region) region of the virus, the section of messenger RNA that contains regulatory regions that influence gene expression and protein function, as well as the coding region that ultimately produces a protein, unless they are outnumbered.

"Normally your immune cells would go in and destroy them but you have this large viral load as they continue to replicate and you have all this abrupt inflammatory response," says Isales, which ultimately results in the cytokine storms that help destroy rather than protect organs. He thinks the reduced number of key microRNA critical to the body attacking the virus is an enabler of the disaster than can follow.

SARS and SARS-CoV-2 sequences used in the study were received from the National Center for Biotechnology Information and the GISAID, an international initiative to share data from the influenza viruses and the SARS-CoV-2 strain. The genome sequence of SARS and SARS-CoV-2 were retrieved from GenBank, the National Institutes of Health's genetic sequence database. The scientists used the whole viral genome sequence for microRNA target analysis.

SARS, or severe acute respiratory syndrome, first surfaced in China and spread worldwide but while it was more deadly than the current coronavirus, it was not as infectious so less people ultimately died than are succumbing to COVID-19, Isales says. Worldwide, 8,098 people were infected with SARS and 774 died, according to the Centers for Disease Control and Prevention. Near the end of the first week in May, there were nearly 1.3 million SARS-CoV-2 cases confirmed in the United States alone and more than 76,000 deaths.

People age 65 and older and people of any age with underlying medical conditions, are considered at higher risk for severe illness from COVID-19, according to the Centers for Disease Control and Prevention. Underlying medical conditions include problems like serious heart conditions, chronic lung disease and moderate to severe asthma, and people with a compromised immune system such as individuals with cancer or who have had an organ transplant, the CDC says. Obesity, diabetes, chronic kidney disease requiring dialysis and liver disease are among the other conditions.

Although they do it differently than humans, plants also have memories. For example, many plants can sense and remember prolonged cold in the Winter to ensure they flower at the right time during the Spring. This so-called "epigenetic memory" occurs by modifying specialized proteins called histones, which are important for packaging and indexing DNA in the cell. One such histone modification, called H3K27me3, tends to mark genes that are turned off. In the case of flowering, cold conditions cause H3K27me3 to accumulate at genes that control flowering. Previous work from the Berger lab has shown how H3K27me3 is faithfully transmitted from cell to cell so that in the Spring, plants will remember that it was cold and that winter is over, allowing them to flower at the right time. But just as importantly, once they've flowered and made seeds, the seeds need to forget this 'memory' of the cold so that they do not flower too soon once winter comes around again. Since H3K27me3 is faithfully copied from cell to cell, how do plants go about forgetting this memory in seeds?

To answer this question, an international team lead by Dr. Michael Borg, a postdoc in the lab of Dr. Frédéric Berger at the Gregor Mendel Institute of the Austrian Academy of Sciences, set out to analyse histones in pollen, hypothesizing that the process of forgetting would most likely occur in the embedded sperm. The researchers were surprised to find that H3K27me3 completely disappeared in sperm. They found that sperm accumulate a special histone that is unable to carry H3K27me3. This ensures that this modification is erased from hundreds of genes, not only those that prevent flowering but also ones which control a large array of important functions in seeds, which are produced once the sperm is carried by the pollen to fuse with the plant egg cell. This phenomenon is called "epigenetic resetting" and is akin to erasing and reformatting data on a hard drive.

"This actually makes a lot of sense from an ecological perspective" says Dr. Borg. "Since pollen can spread over long distances, by wind or bees for example, and much of the "memory" carried by H3K27me3 is related to environmental adaptation, it makes sense that seeds should "forget" their dad's environment and instead remember their mother's, since they are most likely to spread and grow next to mom."

According to Dr. Berger "Like plants, animals also erase this epigenetic memory in sperm, but they do it by replacing histones with a completely different protein. This is one of the first examples of how a specialized histone variant can help reprogram and reset a single epigenetic mark while leaving others untouched. There are many more unstudied histone variants in both plants and animals, and we expect that aspects of this resetting mechanism we have discovered will be found in other organisms and developmental contexts."

Below please find a summary and link(s) of new coronavirus-related content published today in Annals of Internal Medicine. The summary below is not intended to substitute for the full article as a source of information. A collection of coronavirus-related content is free to the public at http://go.annals.org/coronavirus.

1. ACP: Evidence does not support the use of hydroxychloroquine alone or in combination with azithromycin for prophylaxis or treatment of COVID-19

The American College of Physicians (ACP) has issued new Practice Points saying evidence does not support the use of chloroquine or hydroxychloroquine alone or in combination with azithromycin as prophylaxis for COVID-19 or for treatment of patients with COVID19. The ACP Practice Points also state that physicians, in light of known harms and very uncertain evidence of benefit, may choose to treat hospitalized COVID-19 positive patients with chloroquine or hydroxychloroquine alone or in combination with azithromycin in the context of a clinical trial using shared and informed decision-making with patients and their families. ACP's Practice Points are based on a rapid systematic review conducted by the University of Connecticut Health Outcomes, Policy, and Evidence Synthesis Group. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-1998.

Media contacts: To speak with someone from the American College of Physicians, please contact Andrew Hachadorian at AHachadorian@acponline.org or 215-351-2514.

2. False-Negative Rate of RT-PCR-Based SARS-CoV-2 Tests by Time Since Exposure

Tests for severe acute respiratory syndrome coronavirus 2 based on reverse transcriptase polymerase chain reaction (RT-PCR) are being used to "rule out" infection among high-risk persons, such as exposed inpatients and health care workers, but studies suggest that test sensitivity may be low. Researchers from Johns Hopkins Bloomberg School of Public Health estimated the false-negative rate by day since exposure to infection by pooling and modeling data from previously published studies on RT-PCR sensitivity of upper respiratory tract samples of persons who were ultimately confirmed to have COVID-19. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-1495.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, Lauren M. Kucirka, MD, PhD, can be reached at lauren@jhmi.edu or Barbara Benham at bbenham1@jhu.edu.

3. COVID-19 and Outpatient Parenteral Antimicrobial Therapy

Home infusion therapy can provide a safer alternative for exposure to SARS-CoV-2 infection for many vulnerable patients who receive parenteral therapies on an outpatient basis, such as parenteral antimicrobial therapy. Researchers from Washington University School of Medicine and Institute for Public Health, St. Louis, Missouri propose changes to Medicare payment policy, which currently does not adequately reimburse for these services for many patients. Read the full text: https://www.acpjournals.org/doi/10.7326/M20-1774.

Media contacts: A PDF for this article is not yet available. Please click the link to read full text. The lead author, Yasir Hamad, MD, can be reached at yhamad@wustl.edu.

Scientists are working to find ways to monitor ammonia - an increasing species in the atmosphere closely linked to water eutrophication, soil acidity, and biodiversity loss. But measuring ammonia is not easy because ammonia can change from gas to particles quickly in the air.

Although there are accurate methods to determine ammonia in the lab with the aid of a pump, they are unsuitable for long-term measurements and for large-scale surveys in the field, due to the cost, particularly in terms of manpower, and the need for constant power supply.

To overcome these shortcomings, an alternative method was developed to collect ammonia from the atmosphere without the aid of a pump. The method is called passive sampler, in contrast to previous methods using a pump. It can provide a simple and cost-effective tool for monitoring ammonia without power requirement.

However, in a study published in Atmospheric Research on May 3, scientists tested three passive samples used in ammonia collection, and found that the ammonia concentrations were all subject to low bias (13.4-27.5%), compared with a standard reference method using a pump to draw air into an active sampler.

To address this issue, the researchers used classic theory of Fick's law to revisit the effective flow rate of how much ammonia will diffuse onto an acid-coated filter housed in the protective cases of the passive samplers.

The theoretical flow was then temperature- and pressure- corrected with local observations during the sampling campaign in urban Beijing.

"We found the effective sampling flow rate of the passive samplers were all lower than the nominal value provided by the manufacturer," said Yuepeng Pan from Institute of Atmospheric Physics (IAP) of the Chinese Academy of Sciences, lead author of the study. "The inaccurate effective sampling rate in the passive collection samplers was suggested to be the result of incorrect mass transfer correction factors that were not well considered by the manufacturer."

While the underestimation of ammonia concentrations by passive samplers was previously reported, the ammonia isotope compositions (15N/14N) collected by passive samplers were arguably surprising lower than the active reference method, with a large difference of 15.4‰ in the field investigation of urban Beijing.

Prior to this study, scientists had little confidence to tell which data - collected by passive or active samplers - are more suitable in characterizing ammonia isotope composition. But now the low bias can be corrected by adding 15.4‰ to the value of the ammonia isotope compositions obtained from passive samplers in previous studies.

"The large off-set of 15.4‰ was due to a diffusion isotope effect between light ammonia isotope (14N) and heavy ammonia isotope (15N), driven by relative mass differences (one gram per mole)," said Pan. "I believe this study offers a firmer handle on characterizing ammonia sources and therefore enhances our ability of quantifying which emissions may affect increasing ammonia in future."

Plenty of theories, but nobody knows exactly why we sleep. One thing we know for sure: sleepless nights will not help you make it through the day. There have been many studies exploring how sleep works in the brain and what its purposes are. However, how the synapse - the fundamental building block of the brain contributing to the formation of neuronal circuits - works in relation to sleep has been poorly understood. A research team led by Director KIM Eunjoon of the Center for Synaptic Brain Dysfunctions within the Institute for Basic Science (IBS, South Korea), has reported in vivo findings that a presynaptic cell adhesion molecule named PTPδ is crucial for the development of synapses in the developing brain. Thus, the genetic deletion of PTPδ leads to disruptions in structural, functional, and biochemical compositions in the brain of the afflicted mice, resulting in changes in innate behaviors, such as hyper-locomotor activity, increased anxiety, and decreased sleep.

The human brain contains billions of neurons which communicate with each other via synapses. The signals one neuron sends to another via the release of neurotransmitters at presynaptic sites are sensed by neurotransmitter receptors located at postsynaptic sites of other neurons. In turn, networks of neurons determine the expression of all behaviors and bodily functions controlled by the brain. At the core of all these comprehensive networks for brain functions are the synaptic cell adhesion molecules (CAMs). CAMs are essential for regulating the development of synapses by bridging the pre- and postsynaptic sides. To ensure normal development of neuronal circuits and brain functions, it is critical to make appropriate paring of pre- and postsynaptic CAMs, among many different kinds, during the development of young neurons.

The research team focused on finding specific roles of PTPδ, as it was only suspected of playing a key role in synaptic formation. They developed a fluorescent molecule-tagged version of PTPδ, whose expression in the brain allowed precise and clear-cut visualization of the natural location of PTPδ across the brain and down to the position within the synapse with nanometer scale precision. They also adopted conditional deletions of PTPδ to pinpoint the key joint component in synaptic formation. Crucially, the team has demonstrated that disruptions of presynaptic PTPδ interaction with its postsynaptic binding partner IL1RAPL1 cause all key changes in innate behaviors as shown in Figures 2 and 3.

It has been previously shown that the trans-synaptic interaction (the interaction that spans across the synapse from one neuron to the next) depends on a six amino acid-long short peptide sequence (known as meA) within the PTPδ protein. The research team used this knowledge to specifically block the PTPδ-IL1RAPL1 interaction. When the key meA sequence is deleted, leaving the rest of PTPδ functional and intact, IL1RAPL1 is unable bind to PTPδ and therefore unable to stay on the postsynaptic side of a synapse. This leads to a significant decrease in the number of synapses across the brain, disrupting the intricate neuronal circuits that form and determine behavior output such as sleep. They also selectively deleted PTPδ on excitatory neurons and confirmed the hypothesis that the synapse-to-behavior disruptions were indeed localized to excitatory neurons.

The research team also showed that when IL1RAPL1 is unable to bind to PTPδ across the synapse, the chemical composition of IL1RAPL1 itself changes, with near-complete block of a process called tyrosine phosphorylation in its amino acid sequence. This change in the innate property of IL1RAPL1 is accompanied by exclusion of IL1RAPL1 from the synapse. Because IL1RAPL1 is crucial for the maturation of the synapse, this exclusion leads to structural and functional decreases of the synapse. Disruption of the brain at such a fundamental level leads to the increase in anxiety and decrease in sleep seen in the PTPδ-mutant mice.

There have been several studies that linked synaptic CAMs with abnormal mouse behaviors. Notably, this study offers the first comprehensive overview of how CAMs are linked with sleep, a fundamental brain function. In addition, no previous studies have associated a specific pair of pre- and postsynaptic CAMs with sleep or sleep or sleep-related behaviors such as hyperactivity and anxiety. As mutations in the gene coding for PTPδ are associated with numerous psychiatric disorders, such as schizophrenia, attention deficit hyperactivity disorder (ADHD), and restless leg syndrome (a type of sleep disorder) with each of these disorders affecting 1% to 5% of the general population worldwide, this study shines light on how changes in PTPδ may lead to symptoms reminiscent of the aforementioned disorders.

The development of the brain during the embryonic and early postnatal stages are crucial for the proper expression of behavior and brain-related functions. This study shows that even the singular disruption of the PTPδ-IL1RAPL1 interaction, among many possible pairs of pre- and postsynaptic CAMs, has consequences that last the entire lifetime of the organism, such as a permanent reduction of sleep. Given that sleep is essential to survival, the disruption of a single binding pair at the synapse can have such far-reaching consequences speaks of the importance of this discovery, which will further our understanding of how the basic building blocks of the brain influences complex behaviors such as sleep.

n an article published today in Cell Host and Microbe, Professor Subbarao stressed the importance of detecting a neutralising antibody response in recovered COVID-19 patients, and of studies of COVID-19 vaccines in animal models.

Neutralising antibodies prevent infection by binding to a virus and blocking their ability to infect. After an infection, a host can produce neutralising antibodies to protect against future infection.

"The speed with which SARS-CoV-2, the virus that causes COVID-19, has spread around the world and its toll in numbers of cases, severe illness, and death has been staggering," she said.

"However, technological advances have made rapid vaccine development possible. We have to ask ourselves what the new vaccines should aim to achieve - prevent all infection or prevent severe disease and death? In which age group(s)? What effect will vaccines that address these choices have on subsequent epidemics?"

Professor Subbarao was the Chief of the Emerging Respiratory Viruses Section of the Laboratory of Infectious Diseases at the National Institute for Allergy and Infectious Disease at the US National Institutes of Health during the SARS outbreak in 2002-2003, and was central to an important discovery of how neutralising antibodies protect from infection.

"We used mouse experiments to establish the very important principle that neutralising antibodies alone were sufficient to protect them from SARS-CoV infection," Professor Subbarao described.

She also explained the crucial discovery that the 'spike' protein of the virus induced neutralising antibodies, and the importance of animal trials of several SARS vaccine candidates.

Coronavirus particles have a corona (crown) of spike proteins that allow the virus to attach and enter cells.

"The 'spike' proteins of both SARS-CoV and SARS-CoV-2 are related and they attach to the same molecule called ACE 2 on human cells to infect people. We now also know through animal experiments with SARS-CoV-2 that neutralising antibodies protect from reinfection," Professor Subbarao said.

"Two SARS vaccines were evaluated in humans, and a number of promising candidates were tested in pre-clinical studies, but they weren't pursued because SARS didn't re-emerge.

"However, the work on SARS is relevant to the COVID-19 pandemic because the two viruses share several features and many of the principles and experience with SARS vaccines will apply to SARS-CoV-2."

The optimal minimum legal age for non-medical cannabis use is 19 years of age, according to a study published in BMC Public Health.

A team of researchers at the Memorial University of Newfoundland, Canada, investigated how Canadians who started using cannabis at several young ages differed across important outcomes (educational attainment, cigarette smoking, self-reported general and mental health) in later-life.

Dr Hai Nguyen, lead author of the study said: "Prior to legalisation, the medical community recommended a minimum legal age of 21 or 25 for non-medical cannabis use in Canada. This recommendation was based on scientific evidence around the potential adverse impacts of cannabis on cognitive development. However, policymakers feared a high minimum legal age may lead to large underground markets, with those under the legal age continuing to use cannabis illegally. Ultimately, a lower legal age of 18 or 19 was decided across provinces, however there remains ongoing debate and calls to raise the legal age to 21."

To determine whether the age at which people begin to use cannabis may have an impact on later-life outcomes, the authors analysed data from nationally-representative Canadian Tobacco Use Monitoring Surveys (CTUMS) and Canadian Tobacco, Alcohol and Drugs Surveys (CTADS) conducted between 2004 and 2015, which annually interview up to 20,000 individuals aged 15 years and older.

The authors found different optimal minimum legal ages depending on the outcome of interest. For smoking, respondents who first used cannabis aged 19-20 were less likely to smoke cigarettes later in life than those who first used cannabis aged 18, but no significant difference was found in those who started using cannabis at an older age, indicating an optimum legal age of 19.

The number of respondents reporting a high level of completed education was 16% higher among those who first used cannabis between the ages of 21 and 24, relative to those who first used it before age 18, suggesting an optimal minimum legal age of 21.

General health was significantly better among those who started using cannabis aged 18, relative to those who started before age 18, but no significant difference was found among those who started at an older age, suggesting a minimum legal age of 18. However, mental health outcomes were found to be higher among those who first used cannabis aged 19-20 than before age 18, suggesting a minimum legal age of 19.

Dr Nguyen said: "The lower level of completed education reported in those who first used cannabis at an earlier age may reflect poor neurological development or a higher 'drop-out' rate from further education. It is also possible that those who initiate cannabis use early may use it as a gateway for further illicit drug use, resulting in poorer health in later life, which may explain the poor general or mental health scores recorded in the study."

Dr Nguyen said: "Taking into account all measured outcomes, our results indicate that, contrary to the Canadian federal government's recommendation of 18 and the medical community's support for 21 or 25, 19 is the optimal minimum legal age for non-medical cannabis use. Keeping the legal age below 21 may strike a balance between potential increases in underground markets and illegal use, and avoiding the adverse outcomes associated with starting to use cannabis at an earlier age."

The authors caution that as the study used self-reported data, respondents may not have accurately recalled the age at which they first used cannabis. Data was also collected prior to legalization of non-medical cannabis in Canada and the authors were unable to predict the impact of cannabis use after legalization. They suggest that further research is needed to establish potential causal effects between the age at which cannabis is first used and the outcomes measured in the study, and could also focus on additional outcomes such as driving behaviours and street drug use.

Detailed analysis from the epicentre of the Italian COVID-19 outbreak describes increase in cases of rare Kawasaki-like disease in young children, adding to reports of similar cases from New York, USA and South East England, UK. Syndrome is rare and experts stress that children remain minimally affected by SARS-CoV-2 infection overall.

Doctors in the Bergamo province of Italy [1] have described a series of ten cases of young children with symptoms similar to a rare inflammatory disease called Kawasaki Disease appearing since the COVID-19 pandemic arose in the Lombardy region of Northern Italy, in a report published today in The Lancet.

Only 19 children had been diagnosed with the condition in that area in the five years up to the middle of February 2020, but there were 10 cases between 18 February and 20 April 2020. The latest reports could represent a 30-fold increase in the number of cases, although researchers caution that it is difficult to draw firm conclusions with such small numbers.

Eight of the 10 children brought to hospital after 18 February 2020 tested positive for the SARS-coronavirus-2 virus (SARS-CoV-2) in an antibody test. All of the children in the study survived, but those who became ill during the pandemic displayed more serious symptoms than those diagnosed in the previous five years.

Kawasaki Disease is a rare condition that typically affects children under the age of five. It causes blood vessels to become inflamed and swollen. The typical symptoms include fever and rash, red eyes, dry or cracked lips or mouth, redness on the palms of the hands and soles of the feet, and swollen glands. Typically, around a quarter of children affected experience cardiac complications, but the condition is rarely fatal if treated appropriately in hospital. It is not known what triggers the condition but it is thought to be an abnormal immune overreaction to an infection.

Dr Lucio Verdoni, author of the report from the Hospital Papa Giovanni XXIII in Bergamo, Italy, said: "We noticed an increase in the number of children being referred to our hospital with an inflammatory condition similar to Kawasaki Disease around the time the SARS-CoV-2 outbreak was taking hold in our region. Although this complication remains very rare, our study provides further evidence on how the virus may be affecting children. Parents should follow local medical advice and seek medical attention immediately if their child is unwell. Most children will make a complete recovery if they receive appropriate hospital care." [2]

The study authors carried out a retrospective review of patient notes from all 29 children admitted to their paediatric unit with symptoms of Kawasaki Disease from 1 January 2015 to 20 April 2020.

Before the COVID-19 outbreak, the hospital treated around one case of Kawasaki Disease every three months. Between 18 February and 20 April 2020, 10 children were treated for symptoms of the disease. The increase could not be explained by an increase in hospital admissions, as the number of patients admitted during that time period was six fold lower than before the virus was first reported in the area.

Children who presented at hospital with symptoms after 18 February 2020 were older on average (mean age 7.5 years) than the group diagnosed in the previous five years (mean age 3 years). They also appeared to experience more severe symptoms than past cases, with more than half (60%, 6/10 cases) having heart complications, compared with just 10% of those treated before the pandemic (2/19 cases). Half of the children (5/10) had signs of toxic shock syndrome, whereas none of the children treated before February 2020 had this complication. All patients before and after the pandemic received immunoglobulin treatment, but 80% of children during the outbreak (8/10) required additional treatment with steroids, compared with 16% of those in the historical group (4/19).

Two of the patients treated after 18 February 2020 (2/10) tested negative for SARS-CoV-2 on an antibody test. The researchers say the test used is not 100% accurate (95% sensitivity and 85-90% specificity), suggesting these could be false negative results. In addition, one of the patients had recently been treated with a high dose of immunoglobulin, a standard treatment for Kawasaki Disease, which could have masked any antibodies to the virus.

Taken together, the authors say that their findings represent an association between an outbreak of SARS-CoV-2 virus and an inflammatory condition similar to Kawasaki Disease in the Bergamo province of Italy. The researchers say the COVID-related cases should be classified as 'Kawasaki-like Disease', as the symptoms were different and more severe in patients treated after March 2020. However, they caution that their report is based on only a small number of cases and larger studies will be required to confirm the association. They also warn that other countries affected by the COVID-19 pandemic might expect to see a similar rise in cases similar to Kawasaki Disease.

Dr Lorenzo D'Antiga, lead author of the study from the Hospital Papa Giovanni XXIII in Bergamo, Italy, said: "We are starting to see case reports of children presenting at hospital with signs of Kawasaki Disease in other areas hit hard by the COVID-19 pandemic, including New York and South East England [3, 4]. Our study provides the first clear evidence of a link between SARS-CoV-2 infection and this inflammatory condition, and we hope it will help doctors around the world as we try to get to grips with this unknown virus." [2]

Dr Annalisa Gervasoni, another author of the study and a Paediatric Specialist at the Hospital Papa Giovanni XXIII in Bergamo, Italy, said: "In our experience, only a very small proportion of children infected with SARS-CoV-2 develop symptoms of Kawasaki Disease. However, it is important to understand the consequences of the virus in children, particularly as countries around the world grapple with plans to start relaxing social distancing policies." [2]

Writing in a linked Comment, Professor Russell Viner, President of the Royal College of Paediatrics and Child Health and Professor of Adolescent Health, UCL Great Ormond Street Institute of Child Health, UK, (who was not involved in the study), said: "Although the Article suggests a possible emerging inflammatory syndrome associated with COVID-19, it is crucial to reiterate--for parents and health-care workers alike--that children remain minimally affected by SARS-CoV-2 infection overall. Understanding this inflammatory phenomenon in children might provide vital information about immune responses to SARS-CoV-2 and possible correlates of immune protection that might have relevance both for adults and children. In particular, if this is an antibody-mediated phenomenon, there might be implications for vaccine studies, and might also explain why some children become very ill with COVID-19, while the majority are unaffected or asymptomatic."