Earth

Researchers have made progress towards a G7 commitment to establish safe standards for the release of antimicrobials into the environment, by developing a new framework that establishes safe thresholds.

The threat of bacteria developing resistance to antimicrobial drugs (often called antibiotics) used to treat infection is one of the greatest global health challenges, potentially resulting in 10 million deaths per year by 2050.

A major issue is the spread of antimicrobials and resistant bacteria through water systems. When we take antibiotics, 70 per cent passes through our bodies into wastewater. Farm animals are treated with antibiotics which can also end up in aquatic systems through run-off and flooding. University of Exeter research has previously shown that even when antimicrobials are present in these waters at low levels, they can contribute to the evolution of resistant bacteria. These bacteria can make their way into our guts, potentially causing health problems.

Last month, the G7 Climate and Environment Ministers' Meeting Communiqué recognised that the release of antimicrobials into the environment can select for antimicrobial resistance (AMR) and have an impact on human, animal and environmental health. The communique reads: "We note with concern that there are currently no international standards on safe concentrations of antimicrobials released into the environment from, inter alia, pharmaceutical manufacturing, healthcare facility effluent, agriculture and aquaculture. We also acknowledge the work of the AMR Industry Alliance in this regard. We commit to accumulate knowledge on AMR in the environment. We will work with our ministerial colleagues with responsibility for health, food, farming and medicines regulators where independent of government, as appropriate to develop and agree such standards."

Now, in a paper published in Water Research, the Exeter team worked with global pharmaceutical company AstraZeneca to make a significant step towards meeting this need. After reviewing the available evidence in the field, they have developed a framework which effectively provides guidance on how to perform a risk assessment to ensure the levels of antimicrobials released into the environment are safe. Currently there are no thresholds for safe levels of antimicrobials in wastewater and aquatic systems, although the EU and UK government are monitoring the emerging evidence.

Dr Aimee Murray, of the University of Exeter, lead author on the paper, said: "Over the past few years, our research has helped understand the urgent threat posed by the evolution of AMR in our waters and in the environment. We're delighted to see the G7 Climate and Environment Ministers' Meeting commit to taking action. Our new paper is a significant step towards informing policy that can ensure the levels of antimicrobials we release into the environment are safe."

The Exeter team's review summarises and critically appraises the current approaches that study the concentrations of antimicrobials that increase AMR. They have consolidated terminology and recommended how data (including data generated at Exeter) on selection for AMR can best be analysed to establish safe thresholds for release into the environment. By collating and assessing available data, they have recommended what these safe thresholds could be, to enable governments to act to reduce them.

Professor Will Gaze, of the University of Exeter, said: "if we don't take action now, AMR could be a greater threat to humanity than COVID-19 over the coming decades. Our work over the last decade represents a significant contribution to understanding the role of the environment in the evolution and transmission of AMR. There is still uncertainty regarding the complex processes that lead to antimicrobial resistance genes being mobilised from environmental bacteria to human pathogens and how the presence of antimicrobials in natural environments drives this phenomenon."

Professor Jason Snape, Global Head of Environment at AstraZeneca, said: "This framework is the latest output from our partnership with the University of Exeter, which has helped us over the past eight years to establish science-driven, risk-based targets for discharge concentrations for antibiotics, both to meet our commitments as a company and for our industry, addressing critical knowledge gaps in support of science-based policy to address environmental risks associated with AMR."

Leipzig. Soot particles from oil and wood heating systems as well as road traffic can pollute the air in Europe on a much larger scale than previously assumed. This is what researchers from the Leibniz Institute for Tropospheric Research (TROPOS) conclude from a measurement campaign in the Thuringian Forest in Germany. The evaluation of the sources showed that about half of the soot particles came from the surrounding area and the other half from long distances. From the researchers' point of view, this underlines the need to further reduce emissions of soot that is harmful to health and the climate, as the carbon-containing particles still contribute to health hazards and climate warming even over distances of several hundred kilometres.

The results were published in the journal Atmospheric Chemistry and Physics (ACP), an open access journal of the European Geosciences Union (EGU).

Aerosol particles in the atmosphere affect global climate, human health and ecosystems. The chemical composition of atmospheric particles at a given location depends not only on the local environment and sources, but is also influenced by the history of the particles reaching the sampling location. During transport, so-called ageing processes not only change the chemical composition of the particles, but also influence their physical properties (e.g. size distribution, volatility, hygroscopicity, cloud condensation nuclei (CCN) activity and optical properties). The load at a given location is therefore a complex mixture of different sources in combination with a complex transformation process. Carbonaceous aerosol particles predominate in the total mass of particles, consisting of a large number of chemical species and can be divided into organic aerosol (OA) and black carbon (BC). Black carbon is associated with primary emissions from combustion processes from anthropogenic sources (car, domestic heating and industry) or biogenic sources (e.g. forest fires). Not only local sources influence the chemical composition of aerosol particles. Long-distance transport also affects the chemical composition of aerosol particles through the origin of the air masses.

In September/October 2010, extensive measurements took place in Thuringia as part of the "Hill Cap Cloud Thuringia 2010" (HCCT-2010) experiment. The analysis now published examined the chemical composition of aerosol particles and the various sources of carbon-containing particles that reached the measurement site near the village of Goldlauter in the Thuringian Forest, Germany. At that time, a total of about 50 cloud researchers from Germany, France, England and the USA had participated in the measurements in the middle of Germany. The evaluation and chemical analysis of the extensive samples was very time-consuming and took several years. "The data analysis applied made it possible to distinguish local soot emissions dominated by fossil fuel combustion from soot transported from great distances," explains Dr Laurent Poulain from TROPOS. "But a physical effect also helped us: Over the course of their short lives, soot containing particles grow. The bigger this particle is, the older it is and the longer it must have been travelling in the atmosphere." The impactor samples were therefore divided into two categories: Carbon in particles smaller than 400 nanometres is relatively young and comes from local sources. Carbon in particles larger than 400 nanometres is relatively old and comes from distant sources. This allowed local soot emissions to be estimated at 48 per cent and soot from distant sources at 52 per cent.

In another study from winter 2016/17, TROPOS researchers were already able to estimate the share of transboundary particulate matter: Particulate matter of the PM10 size class from long-distance transport from Eastern Europe contributed 44 to 62 per cent of the total PM10 particulate matter at rural locations in Eastern Germany, according to a study for various state environmental offices. The main sources were combustion emissions, probably from wood and coal-fired heating systems. With the study now published, it is clear that even for soot, which accounts for only a portion of PM10 fine particulate matter, the relationship between ambient and remote sources is similar: about half of the soot comes from the local environment and the other half from long-distance transport across the continent.

The new findings underline the need to set Europe-wide limits for soot. In spring 2021, the EU Parliament called on the EU Commission to introduce EU-wide standards for ultrafine particulate matter, soot, mercury and ammonia, because although these substances have a negative impact on human health, they are not yet regulated by EU air quality standards. The EU Air Quality Directive is to be updated by 2022. A public consultation is planned for autumn 2021.

However, soot does not only have a negative impact on human health. It is becoming increasingly clear that soot also contributes to global warming by causing the dark particles to absorb light or contribute to cloud formation. According to the latest report of the Intergovernmental Panel on Climate Change (IPCC), there are still large gaps in our knowledge about the quantities and distribution of soot in the atmosphere, which the new report aims to reduce. The IPCC will adopt and publish its new assessment report ("AR6 Climate Change 2021: The Physical Science Basis") in early August 2021. Tilo Arnhold

The type of material present under glaciers has a big impact on how fast they slide towards the ocean. Scientists face a challenging task to acquire data of this under-ice landscape, let alone how to represent it accurately in models of future sea-level rise.

"Choosing the wrong equations for the under-ice landscape can have the same effect on the predicted contribution to sea-level rise as a warming of several degrees", says Henning Åkesson, who led a new published study on Petermann Glacier in Greenland.

Glaciers and ice sheets around the world currently lose more than 700,000 Olympic swimming pools of water every day. Glaciers form by the transformation of snow into ice, which is later melted by the atmosphere in summer, or slides all the way into the sea. With climate change, glaciers are breaking up and drop icebergs into the ocean at an accelerating pace. Exactly how fast depends to a large extent on the bed below all the ice. Glaciers conceal a landscape under the ice covered by rocks, sediments and water. A new study shows that the way we represent this under-ice landscape in computer models means a great deal for our predictions of future sea-level rise. More specifically, how we incorporate the friction between the ground and the ice sliding over it in glacier models is what affects our predictions. This was found by a team of Swedish and American scientists, when they simulated the future of Petermann Glacier, the largest and fastest glacier in northern Greenland.

Petermann is one of the few glaciers in the northern hemisphere with a remaining ice tongue, a type of floating glacier extension otherwise mainly found in Antarctica, where they are called ice shelves. These floating extensions have been found to be exposed to warm subsurface water flowing from the open ocean towards the glaciers. This happens both in Antarctica and in many fjords around Greenland, including the Petermann Fjord.

"Peterman lost 40% of its floating ice tongue over the last decade. It still has a 45 km tongue, but we found that a slightly warmer ocean than today would lead to its break up, and trigger a retreat of the glacier", says Henning Åkesson, a postdoctoral researcher at Stockholm University who led the study.

Many glaciers in Greenland and Antarctica flow towards the ocean much faster than they did a few decades ago, and therefore contribute more to global sea-level rise. Scientists have therefore mobilized great efforts into learning what is going on in these environments. This has spurred new insights into the landscape under glaciers and the shape of the seafloor where they drain. We now also know much more about what happens to the ice when glaciers meet the sea.

Still, the remote polar regions are notoriously difficult to study because of sea ice, icebergs, and often harsh weather. The under-ice landscape is a particular challenge because, frankly, it is hard to measure something covered by a kilometer of ice on top. Even in areas of known under-ice topography, describing its physical properties using mathematical equations is difficult. Computer models are therefore still somewhat in the dark when it comes to how to represent things like sediments, rocks, ponds and rivers under glaciers in the equations that describe ice flow. These equations are ultimately the foundation of the models used by the IPCC to estimate how fast glaciers flow and how much sea levels will rise under future climate warming.

"As we said, choosing the wrong equations for the under-ice landscape can have the same effect on the contribution to sea-level rise as a warming of several degrees", Åkesson says.

"In fact, predicted sea-level rise for this Greenland glacier can quadruple depending on how we represent friction under the ice. We still don't know which way is the best, but our study illustrates that ice-sheet models still need to progress in this respect, in order to improve our estimates of mass loss from Earth's polar ice sheets."

Washington, D.C. - June 9, 2021 - The Pfizer COVID-19 vaccine is protective against several SARS-CoV-2 variants that have emerged, according to new research presented in the journal mBio, an open-access journal of the American Society for Microbiology. While this is good news, the study also found that the only approved monoclonal antibody therapy for SARS-CoV-2 might be less effective against SARS-CoV-2 variants in laboratory experiments.

"The vaccines provide very strong protection against the earlier forms of the virus as well as the newer variants. This is an important point because I have heard people say that they don't think there is a reason to get vaccinated, because the vaccine isn't going to work against the variants, but that is not true--the vaccine will work against the variants," said Nathaniel "Ned" Landau, Ph.D., professor in the Department of Microbiology at the NYU Grossman School of Medicine, in New York City.

To conduct their research, Dr. Landau and colleagues in the NYU Department of Microbiology and NYU Langone Vaccine Center created a panel of pseudotype viruses that combined the HIV virus and SARS-CoV-2 spike protein. Pseudotype viruses are replication-defective viral particles formed with a structural and enzymatic core from one virus and the envelope glycoprotein of another, that have been proven to be useful as research tools with little associated risk. "The SARS-CoV-2 spike protein is important, because it is the only structure on the virus that is exposed to the outside. The spike protein is what sticks out from the virus; it is what the immune system recognizes and what allows the virus to stick onto target cells," said Dr. Landau.

There are 2 reasons the researchers chose HIV to create their chimeric viruses. First, HIV is not particular about incorporating the HIV spike protein; it will take most any virus spike protein. Second, the HIV virus has been engineered to carry 2 reporter genes that allow researchers to study virus entry, antibody binding, and antibody neutralization. When the virus infects a cell, the cell turns green and produces luciferase, the enzyme that makes fireflies light up at night. This provides a quick and easy way to count how many cells have been infected. "The spike protein-pseudotyped lentiviruses are extremely useful experimental tools. They were developed in the course of HIV research. They are less biohazardous and easier to work with in the lab," said Dr. Landau.

The researchers created a panel of pseudotype viruses using the spike proteins from 6 different variants of SARS-CoV-2: the B.1.1.7 lineage variant identified in the United Kingdom, the B.1.351 lineage variant identified in South Africa, the B.1.1.248 lineage variant identified in Brazil, the COH.20G/677H lineage variant identified in Columbus Ohio, the 20A.EUs variant identified in Spain and later found elsewhere in Europe, and the Mink cluster 5 spike proteins located in minks in Denmark. They then mixed these pseudotype viruses with serum from either people who had received the Pfizer SARS CoV-2 vaccine or people who had already had COVID-19.

The researchers found that convalescent sera neutralize pseudotyped viruses with the 6 variants with only a small loss in titer. They also found that the Pfizer BNT162b2 vaccination worked just as well against the majority of variants as the earlier virus, but the vaccine neutralized the South African variant and the Brazil variant with a 3-fold decrease in titer, an effect attributable to the mutation E484K. Dr. Landau said that people should not be concerned about these results, however.

"Our interpretation of the results is that the vaccine antibodies are very powerful, and even if you lose 3-fold of the titer, there is still plenty of antibody there to neutralize the virus. We believe the findings demonstrate that the vaccines will remain protective against the variants that we tested," said Dr. Landau. "While it's not reported in this paper, we have done the same experiments with the Moderna vaccine and got similar results."

In another experiment, the researchers tested Regeneron Pharmaceuticals REGN-COV2, a 2 recombinant monoclonal antibody cocktail consisting of casirivamab and imdevimab, that has been effective at decreasing symptoms of individuals with COVID-19 and keeping them out of the intensive care unit. The researchers found that casirivamab had lost some of its neutralizing activity against the South African and Brazilian variants and the cocktail was 9- to 15-fold decreased in titer.

"One of the Regeneron antibodies is affected by the E484K mutation, and as a result the cocktail loses some of its neutralizing activity," said Dr. Landau. "The question with this work is 'how do the laboratory findings translate into clinical effects, that is what will happen when you treat a patient infected with one of the variants?' We cannot say for sure. We will only know when the clinical data comes in."

The team say their findings have implications for the treatment of viruses in future.

Researchers from the Universities of York and Leeds, collaborating with the Hilvert Laboratory at the ETH Zürich, studied the structure, assembly and evolution of a 'container' composed of a bacterial enzyme.

The study - published in the journal Science - details the structural transformation of these virus-like particles into larger protein 'containers'.

It also reveals that packaging of the genetic cargo in these containers becomes more efficient during the later stages of evolution. They show that this is because the genome inside evolves hallmarks of a mechanism widely used by natural viruses, including Covid-19, to regulate their assembly. That mechanism was a joint discovery of the York and Leeds team. Professor Reidun Twarock, from the University of York's Departments of Mathematics and Biology, and the York Cross-disciplinary Centre for Systems Analysis, said: "Using a novel interdisciplinary technique developed in our Wellcome Trust funded team in Leeds and York, we were able to demonstrate that this artificial system evolved the molecular hallmarks of a 'virus assembly mechanism', enabling efficient packaging of its genetic cargo."

In its evolution, the artificial virus-like particle efficiently packages and protects multiple copies of its own encoding messenger RNA.

Professor Peter Stockley from the University of Leeds' Astbury Centre for Structural Molecular Biology, said "What's remarkable is this artificial virus-like particle evolves to be more efficient in packaging RNA. Our collaboration shows that following the evolutionary steps the encapsidated messenger RNAs incorporate more Packaging Signals than the starting RNAs. In other words, the phenomenon we have been working on in natural viruses "evolves" in an artificial particle, and the results in this paper therefore describe a process that may have occurred in the early evolution of viruses. This understanding enables us to exploit these containers as delivery vehicles for gene therapeutic purposes."

It's often cancer's spread, not the original tumor, that poses the disease's most deadly risk.

"And yet metastasis is one of the most poorly understood aspects of cancer biology," says Kamen Simeonov, an M.D.-Ph.D. student at the University of Pennsylvania Perelman School of Medicine.

In a new study, a team led by Simeonov and School of Veterinary Medicine professor Christopher Lengner has made strides toward deepening that understanding by tracking the development of metastatic cells. Their work used a mouse model of pancreatic cancer and cutting-edge techniques to trace the lineage and gene expression patterns of individual cancer cells. They found a spectrum of aggression in the cells that arose, with cells that were likely to remain in place at the primary tumor at one end and those that were more likely to move to new sites and colonize other tissues at the other end.

Of the cells that eventually became metastatic and grew in tissues and organs beyond the pancreas, the majority shared a common lineage, the researchers discovered.

"By building a precision tool for probing cancer metastasis in vivo, we're able to observe previously inaccessible types of information," says Simeonov. "We were able to use this lineage tracing approach to rank cells based on how metastatic they were and then relate these differences in behavior to gene expression changes."

The group's findings, published in the journal Cancer Cell, suggest that it's not only genetic mutations that can drive cancer's spread; the single-cell RNA profiling results underscore that gene expression patterns--which genes cells are turning on and off--play a key role in disease outcomes.

Fusing novel techniques

While scientists have characterized hundreds of genetic mutations associated with driving normal cells to become cancerous, they haven't had the same success in identifying mutations that turn cancerous cells metastatic.

One possibility may be that the process is dependent on factors other than mutations, or depends on so many abnormalities grouped together that the signature is hard to resolve.

In order to better understand the biological changes that accompany metastasis, Simeonov, Lengner, and colleagues aimed to meticulously track this process, using evolving barcoding, also referred to as CRISPR lineage tracing, which enables reconstruction of cell family trees. They paired this with single-cell RNA sequencing to get a picture of the genes being turned on in each cell.

To track lineage, the researchers developed a new method employing CRISPR/Cas9 to mutagenize synthetically introduced DNA sequences, serving as cellular barcodes. These engineered cancer cells were then injected into a mouse and allowed to metastasize. While the cancer develops and spreads in the host mouse, the cellular barcodes are randomly "edited" by CRISPR/Cas9. The resulting barcode editing patterns can be used, Simeonov says, "to reconstruct phylogenetic trees of the cancer cells as they've proliferated and metastasized throughout the body."

Looking at roughly 28,000 cancer cells across multiple organs of two mice, the researchers were able to see which genes each cell was turning on as the cancer spread from the pancreas to other organs and tissues. They also tracked where the cells were disseminating in the body to see if particular lineages were more likely to be metastatic than others.

"So for all of these cells, we know where they were located in the body, we have a metric for how well they metastasized, and then we also have their transcriptomes," or catalog of RNA molecules, Simeonov says.

Spectrum of aggression

When the research team examined these pools of data together, they were surprised to find that about half of the clones, or distinct populations of cancer cells, were confined to the primary tumors.

And when they looked at the clones that had spread, they found just one dominant clone in each mouse.

"Surprisingly, despite using an aggressive cancer cell line that should be readily able to metastasize, we found that one clone dominated metastastic sites," Simeonov says. "We were expecting more equitability between clones."

The transcriptome profile of this dominant clone in the metastases, as well as other clones that spread from the primary tumor, were distinct from one another and from clones that stayed confined to the primary tumors. The gene expression data from this aggressive clone revealed that it had turned on genes associated with what's known as the epithelial-mesenchymal transition (EMT), a process believed to lend cancer some of its aggressive qualities. Across the entirety of clones, the team found cells occupied different places in the EMT spectrum, from having many epithelial genes expressed to having many mesenchymal genes expressed. "Cells appeared to exist along a continuum of EMT states," Simeonov says.

The genetic profile of the more aggressive cells turned up numerous matches with genes associated with human cancer, some of which have been predictive of reduced survival. The researchers also found that, in a particularly aggressive clone from the second mouse, a gene family associated with cancerous properties, such as cell migration and the ability to enter and exit blood vessels, was dramatically overexpressed compared to other clones.

"The expression of this gene family appeared to propagate across distinct populations and enhance the ability to metastasize in a process potentially complementary to EMT," says Simeonov.

In future work, Simeonov, Lengner, and colleagues hope to further their studies of the process of metastasis, while also exploring new avenues for applying this lineage-tracing tool, such as examining the process of development, stem cell biology, or the regeneration of lung or intestinal tissue.

"We hope that our approach enables previously inaccessible questions to be explored and answered," Simeonov says.

WOODS HOLE, Mass. -- Many animals have evolved camouflage tactics for self-defense, but some butterflies and moths have taken it even further: They've developed transparent wings, making them almost invisible to predators.

A team led by Marine Biological Laboratory (MBL) scientists studied the development of one such species, the glasswing butterfly, Greta oto, to see through the secrets of this natural stealth technology. Their work was published in the Journal of Experimental Biology.

Although transparent structures in animals are well established, they appear far more often in aquatic organisms. "It's an interesting biological question because there just aren't that many transparent organisms on land," notes lead author Aaron Pomerantz, a PhD candidate in Integrative Biology at the University of California, Berkeley. "So we asked the question, what is the actual developmental basis of how they create their transparent wings?"

Butterfly wings are known for their colorful patterns, created by tiny, overlapping, chitinous scales that reflect or absorb various wavelengths of light to produce colors. Pomerantz says that although scale coloration has been intensively studied, investigating the developmental origins of transparency in land-based butterflies hadn't been done before. "Transparency is sort of the opposite of color," he says.

Pomerantz and his co-authors, including his PhD advisor and MBL Director Nipam Patel, were inspired by the work of students in MBL's Embryology course, in which Patel teaches. "I decided to bring some of the transparent butterfly and moth species I had in my collection, which I never really looked at in detail, to the course and present it as a challenge for the students to look at how these wings were transparent," Patel says. "A group of students took that on by imaging the wings with various microscopes. And they realized that pretty much any way you could think to make the wing transparent, some butterfly or moth had figured out how to do it. That's what got us looking in more detail at the development of transparency."

Building on that work, the researchers used confocal and scanning electron microscopy to construct a developmental time scale of how transparency emerges in Greta oto, from the pupal stage to adulthood. They found that the glasswing butterfly's wings develop differently than opaque species, with a lower density of precursor scale cells in the areas that will later develop as transparent. At a very early stage, scale growth and morphologies differed, with thin, bristle-like scales developing in transparent regions and flat, round scale morphologies within opaque regions.

"What Greta oto does is to make fewer scales and to make them in these very different, bristle-like shapes," Patel explains. "But getting the scales out of the way is only part of the problem of creating transparency. Aaron also made a series of observations about nanostructures on the wing that prevent glare in bright sunlight. When light hits these little arrays of nanostructures, it doesn't reflect off -- it goes straight through. So that gives much better transparency," he says.

"As humans, we think we're so brilliant because we figured out how to put anti-glare coating on glass, but butterflies basically figured that out tens of millions of years ago," Patel says.

Unusual wing scales and nanostructures are only part of the story. A second layer of waxy hydrocarbon nanopillars lies atop the wing surface, providing further anti-reflective properties. The researchers examined the reflectivity of the wings before and after removing the waxy layer with hexane.

"We measured the amount of light that reflected off the wing," says Pomerantz. "Those experiments demonstrated that that upper layer was very important for helping to reduce that glare." Biochemical analysis showed that the waxy layer is mostly composed of long chain n-alkanes, similar to those found in other insect species. "They're primarily thought of as something that helps prevent an insect from drying out or desiccating. But in this case, it seems like they're used for these anti-glare properties as well."

Future research directions may include delving more deeply into the how these transparent structures evolved. Pomerantz points out that "if we can learn more about how nature creates new types of nanostructures, that can be very informative for human applications." The work is making the secrets of natural transparency considerably less opaque.

Chestnut Hill, Mass. (6/10/2021) - A British man who rejected the standard of care to treat his brain cancer has lived with the typically fatal glioblastoma tumor growing very slowly after adopting a ketogenic diet, providing a case study that researchers say reflects the benefits of using the body's own metabolism to fight this particularly aggressive cancer instead of chemo and radiation therapy.

Published recently in the journal Frontiers in Nutrition, the report is the first evaluation of the use of ketogenic metabolic therapy (KMT) without chemo or radiation interventions, on a patient diagnosed with IDH1-mutant glioblastoma (GBM). Ketogenic therapy is a non-toxic nutritional approach, viewed as complementary or alternative, that uses a low-carbohydrate, high-fat diet to manage a range of cancers, including glioblastoma.

In this particular case, the patient's tumor contained a mutation, known as the IDH1. This mutation is acquired by chance and is known to improve overall survival. So the findings are particularly relevant to other patients whose tumors contain this mutation, according to Boston College Professor of Biology Thomas Seyfried, a co-author of the report and a leading researcher who has long advocated the benefits of KMT to treat disease.

"As GBM, like most malignant cancers, is dependent on fermentation for energy synthesis and survival, the simultaneous restriction of fermentable fuels, such as glucose and glutamine, while elevating non-fermentable ketone bodies, offers a non-toxic therapeutic strategy for managing GBM," said Seyfried. "Further studies will be needed to test this hypothesis in other patients diagnosed with GBM."

Glioblastoma kills about 15,000 people each year and remains largely unmanageable. While the standard of care has shifted to new immuno-therapies, the median survival time of 11 to 15 months for GBM has not improved significantly for more than 100 years, according to the co-authors.

A number of high-profile cases have illustrated the deadly progression of GBM. The late U.S. Sen. John McCain was diagnosed at age 80 with glioblastoma in July 2017, and died in August 2018. U.S. Sen. Edward M. Kennedy lived for a year after his diagnosis with GBM, dying at age 77. Beau Biden, son of U.S. President Joe Biden, was diagnosed at age 44 with GBM in August 2013, and died in May 2015.

The current standard of care for GBM involves surgical resection, radiation, and chemotherapy, which have been shown in studies to result in significant toxicity. However, large-scale clinical trials for alternative therapies are difficult to initiate, leading researchers to carefully examine individual cases.

The patient in this case was diagnosed with glioblastoma in 2014 and eschewed the traditional standard of care and instead embarked on a self-directed ketogenic diet -- low in carbohydrates and high in fat -- in an effort to manage his cancer.

The researchers found "the patient's tumor continued to grow very slowly over a three-year period without expected vasogenic edema until 2017," according to Seyfried and his co-authors, Boston College researcher Purna Mukherjee, Aditya Shivane, MD, of University Hospital Plymouth NHS Trust, in the United Kingdom, U.S.-based nutritionist Miriam Kalamian, Joseph Maroon, MD, of the University of Pittsburgh, and Giulio Zuccoli, MD, of the Drexel University School of Medicine

At that point, the patient underwent "surgical debulking" of his tumor. The pathology specimen confirmed the diagnosis of GBM and that the patient's tumor also contained the IDH1 mutation.

"Following surgery, the patient continued with a self-administered ketogenic diet to maintain low Glucose Ketone Index (GKI) values, indicative of therapeutic ketosis," the researchers report. "In light of continued slow progression of the residual tumour, the patient intensified his KMT starting in October, 2018 with inclusion of mindfulness techniques to reduce stress. While Magnetic Resonance Imaging (MRI) shows slow interval tumor progression, the patient remains alive with a good quality of life at the time of this report." He is now at 82 months from original diagnosis.

"We were surprised to discover that KMT could work synergistically with the IDH1 mutation to simultaneously target the two major metabolic pathways needed to drive the growth of GBM," said Seyfried. "Glucose drives the glycolysis pathway, while glutamine drives the glutaminolysis pathway."

He added: "No tumor, including GBM, can survive without glucose and glutamine. Our study has identified a novel mechanism by which an acquired somatic mutation acts synergistically with a low carbohydrate, high fat diet to provide long-term management of a deadly brain tumor."

Despite the compelling interest in such individual case studies, the co-authors note: "We cannot predict if the therapeutic response to KMT seen in our GBM patient will also be seen in other similarly treated GBM patients. For those GBM patients not fortunate enough to have acquired the spontaneous IDH1 mutation in their tumour, glutamine targeting drugs used with KMT will be necessary to reduce tumour growth."

The researchers noted that additional studies they've conducted have shown that the simultaneous targeting of glucose and glutamine availability, using KMT and the a pan-glutaminase inhibitor - known as 6-diazo-5-oxo-L-norleucine (DON) - can significantly prolong survival in preclinical syngeneic glioblastomas in mice. Earlier research has shown that ketogenic diets can facilitate delivery of small-molecule therapeutic drugs through the blood brain barrier without toxicity.

Climate change exerts great pressure for change on species and biodiversity. A recent study conducted by the University of Helsinki and the Finnish Environment Institute indicates that the few moth and butterfly species (Lepidoptera) capable of adjusting to a changing climate by advancing their flight period and moving further north have fared the best in Finland. In contrast, roughly 40% of Lepidoptera species have not been able to respond in either way, seeing their populations decline.

Climate change is bringing about rapid change in Finnish nature - can species keep up with the pace? Adjusting to climate change can manifest through earlier phenology such as moth and butterfly flight periods, bird nesting, or plant flowering taking place earlier than before. Species can also adjust by shifting their range further north, as individuals relocate to new areas where conditions have become favourable.

The researchers emphasise that, to preserve biodiversity as climate change intensifies, it is of utmost importance to ensure sufficiently extensive, interconnected and habitats of high-quality which make it possible for species to adjust to the challenges generated by climate change.

The study carried out by the University of Helsinki and the Finnish Environment Institute compared temporal shifts in the flight period of 289 moths and butterflies and spatial shifts in their northern range boundary, as well as changes in abundance over a roughly 20-year period.

"Roughly 45% of the species that we studied had either moved northward or advanced their flight period," says Postdoctoral Researcher Maria Hällfors from the University of Helsinki. "They fared much better than the 40% of the species which had not responded in either way. On average, the populations of these poorly responding species had declined. The largest increase in abundance was seen in the 15% of the species that both moved northward and advanced their flight. This demonstrates that the ability to respond to a changing environment is vital for species."

Few species have advanced their phenology

Another interesting finding was the fact that while nearly half of the species had moved northward, only 27% had advanced their flight period.

"This finding deviates from observations made elsewhere in Europe where advancing the flight period has been much more common among Lepidoptera," says Senior Researcher Juha Pöyry from the Finnish Environment Institute.

In Finland, the species that have advanced their flight the most are the ones that overwinter as adults, including the European peacock butterfly. In fact, it appears that Lepidoptera species living in Finland respond more readily by expanding their ranges northward compared to advancing their flight. Species which are found further north than before include the antler moth and the scarce copper.

"It may be that the increasing light in the spring is a more important cue for butterflies and moths to start their flight than temperature on its own," Pöyry adds.

Sufficient habitats are vital

A potential explanation for the infrequency of species responding optimally, that is, by both advancing their flight and moving northward, could be the scarcity of suitable habitats.

"For organisms to be able to respond to climate change by shifting their range further north, sufficient amounts of suitable habitats of high-quality are needed," says Mikko Kuussaari, Senior Researcher at the Finnish Environment Institute.

The amount of habitats important for many moth and butterfly species has decreased, resulting in population decline for many of them. For example, many butterfly species have suffered from a decrease in meadows.

"Declining populations are usually not able to provide a sufficient basis for the species to spread to new areas. Small populations also contain less genetic diversity that could help the local populations adjust by changing the timing of their flight. " Kuussaari adds. Indeed, safeguarding biodiversity requires, above all, the maintenance of sufficiently large and interconnected habitats of high-quality .

Long-term monitoring enables research

The study utilised data on Lepidoptera flight periods collected in two long-term monitoring projects coordinated by the Finnish Environment Institute. Of the two, the Finnish national moth monitoring scheme was launched in 1993 and the butterfly monitoring scheme in agricultural landscapes in 1999. A dataset of citizen observations openly available through the Finnish Biodiversity Information Facility was utilised to calculate species range boundary shifts.

"Without such long-term monitoring schemes and the great contribution of volunteer butterfly and moth enthusiasts in collecting observations, as well as collaboration between different research organisations, it would be impossible to carry out these kinds of analyses encompassing hundreds of species," says Associate Professor Marjo Saastamoinen from the University of Helsinki.

Most of Asia, Europe, North America and South America have never experienced heatwave conditions that would prohibit electric fans from being a safe, effective and clean alternative to air conditioning, according to a new study.

The biophysical modelling study, published in The Lancet Planetary Health, challenges outdated public health guidance that discourages fan use in temperatures higher than 35 degrees Celsius / 95 degrees Fahrenheit.

Based on human studies carried out at the University of Sydney's Thermal Ergonomics Laboratory, the researchers developed a model to determine the humidity-dependent temperature thresholds at which fans could become detrimental, providing conditions that exacerbate heat stress.

"The effectiveness of a fan depends on temperature and relative humidity and our previous human studies have shown that it is only when the air temperature is very high and humidity is extremely low that fans can be detrimental," said senior author Professor Ollie Jay, Professor of Heat and Health at the University of Sydney's Faculty of Medicine and Health and Charles Perkins Centre.

"In this study we were able to model the impact of different conditions based on historic weather data. We have shown that for younger adults fan use could be recommended most of the time in most regions around the world, except for those living in extremely hot and arid areas.

"This is extremely important as air conditioning, both directly and indirectly contributes to greenhouse gas emissions. Electric fans on the other hand require 30 to 50 times less energy to operate. They are more sustainable and more accessible particularly in low- and middle-income countries."

Key findings

Based on weather data from January 1, 2007 to December 31, 2019 the researchers found that contrary to many public health recommendations - including from the World Health Organization (WHO) - electric fan use for effective cooling without air conditioning could have been universally recommended for young healthy people during peak heatwave conditions in all populous cities in Bangladesh, China, Japan, Philippines, Indonesia, Canada, eastern regions of the USA, all of South America and Oceania and most of Europe (excluding some Mediterranean cities).

Fan use alone should not have been routinely recommended during hot weather in northern India, Pakistan, the Middle East, and the southwestern regions of the USA, because it would have regularly worsened heat stress.

The researchers note that alternative cooling strategies may be required in some regions for healthy older adult and particularly those taking anticholinergic medications (a class of drugs that block the Acetylcholine, a neurotransmitter) that impair sweating, the primary way in which our bodies cool down.

The authors conclude by demonstrating that worldwide guidance for electric fan use during heatwaves should be modified.

Specifically, they propose that the simplified fan use temperature threshold of 35?C currently recommended by the WHO should be increased to 39?C for young healthy adults, 38?C for healthy adults older than 65 years, and 37?C for older adults taking anticholinergic medication.

Lead author Dr Nathan Morris, a post-doctoral researcher in environmental physiology at the University of Copenhagen, Denmark said: "Our hope is that public health authorities will modify their current heatwave recommendations to align with the latest scientific evidence. Broadening the use of these devices during heatwave conditions has the potential to both drastically reduce peak power demands and offer a low-resource alternative for those who do not have access to air conditioning."

Bristle worms are found almost everywhere in seawater, they have populated the oceans for hundreds of millions of years. Nevertheless, some of their special features have only now been deciphered: Their jaws are made of remarkably stable material, and the secret of this stability can now be explained by experiments at TU Wien in cooperation with Max Perutz Labs.

Metal atoms, which are incorporated into the protein structure of the material, play a decisive role. They make the material hard and flexible at the same time - very similar to ordinary metals. Further research on this class of materials aims at producing novel, industrially usable materials in a natural way.

Individual metal atoms

"The materials that vertebrates are made of are well researched," says Prof. Christian Hellmich from the Institute of Mechanics of Materials and Structures at TU Wien. "Bones, for example, are very hierarchically structured: There are organic and mineral parts, tiny structures are combined to form larger structures, which in turn form even larger structures."

It's different with bristle worms. Their jaws are extremely strong and unbreakable, but they do not contain mineral granules like vertebrate bones do. Instead, they contain metals. Of course, this has nothing to do with pure metal objects such as gold teeth or artificial hips made of titanium: The bristle worm uses metals such as magnesium or zinc in the form of individual atoms that are incorporated into a protein structure.

"On its own, the fact that there are metal atoms in the bristleworm jaw does not explain its excellent material properties," says Christian Hellmich. The typical properties known from everyday metals - apart from their hardness and elasticity, above all their toughness - are ultimately only created through the interaction of many atoms. Sliding surfaces are created along which the atoms move against each other. This can be investigated with so-called nanoindentation tests: A force is exerted on the material in a precisely defined way and then the resulting deformations are studied. Surprisingly, it turned out that the material of the bristleworm jaw behaves very similarly to metal.

An ancient high-performance material

"The construction principle that has made bristle worm jaws so successful apparently originated about 500 million years ago," says Florian Raible of the Max Perutz Labs, a joint venture of the University of Vienna and the Medical University of Vienna. "The metal ions are incorporated directly into the protein chains and then ensure that different protein chains are held together." In this way, the bristle worm can produce three-dimensional shapes from a particularly stable protein matrix.

At the same time, this structure also allows for deformation: When an external force is exerted on the material, the protein chains can slide past each other. The material allows elastoplastic deformations, rather than being brittle and fragile.

"It is precisely this combination of high strength and deformability that is normally characteristic of metals," says Luis Zelaya-Lainez, the study's lead author, who used materials science techniques to examine the tiny jaws. "Here we are dealing with a completely different material, but interestingly, the metal atoms still provide strength and deformability there, just like in a piece of metal."

Whereas industrially manufactured metals can only be produced using a large amount of energy, the bristle worm achieves a similar feat in a much more efficient way. "Biology could serve as inspiration here, for completely new kinds of materials," Hellmich hopes. "Perhaps it is even possible to produce high-performance materials in a biological way - much more efficiently and environmentally friendly than we manage today."

The fairy circles of the Namib are one of nature's greatest mysteries. Millions of these circular barren patches extend over vast areas along the margins of the desert in Namibia. In 1979, G.K. Theron published the first research about their origin. His hypothesis was that poisonous substances from Euphorbia damarana leaves induced fairy circles. As part of a new study, scientists from the University of Göttingen and the Gobabeb Namib Research Institute located the original euphorbia plants that were part of Theron's study. Four decades later, the researchers are now able to conclusively disprove Theron's original hypothesis. Their results were published in the journal BMC Ecology and Evolution.

In the late 1970s, South African botanist Theron noticed several dying and decomposing shrubs of euphorbia in the Giribes area of north-western Namibia. He therefore proposed that poisonous substances from the leaves of this plant could kill the grasses and induce fairy circles and his hypothesis was published in 1979. As part of the current study, scientists went back to this same area and managed to locate the original metal pins that marked the plants. In 2020, the research team documented these remote sites in detail for the first time, using ground-based photography as well as high-resolution drone imagery and historic satellite images.

The researchers show that none of the marked euphorbia locations developed into a fairy circle. Instead, long-lived grass tussocks were growing around all the metal pins. This runs contrary to the hypothesis that poisons from euphorbia inhibited the growth of other plants because these grasses survived. Given that the euphorbia hypothesis proposes that only dead and decaying shrubs would induce a barren patch, the researchers also measured the sizes of the dying euphorbias and compared them to the sizes of fairy circles in the same study plots. As well as in Giribes, this second part of the study was also carried out at Brandberg. In both regions, the diameters of decaying euphorbias could not explain the sizes of the much smaller or the larger fairy circles. In a third part of the study, the spatial patterns of the fairy circles were directly compared to the patterns of euphorbias within the same areas to investigate a potential link between both distributions in the regions Giribes, Brandberg and Garub. However, the patterns of shrubs and circles did not match: in four out of five plots the patterns differed significantly, with the circles being regularly distributed while the euphorbias were predominantly clustered. Hence the process that creates the pattern of fairy circles is different from the process that creates the pattern of the euphorbias.

Dr Stephan Getzin, Department of Ecosystem Modelling at the University of Göttingen, summarizes, "When Theron published his original euphorbia hypothesis more than four decades ago, he was a pioneer in fairy-circle research: almost nothing was known about them at that time. Today, however, we see the long-term outcome of his early experiment and - based on our detailed field observations - we have to reject the euphorbia hypothesis." Getzin explains, "Disproving hypotheses about the origin of fairy circles is an important step in solving their mystery because it helps advance our scientific understanding. It enables us to identify more probable mechanisms which explain these stunning formations as well as other fascinating biological phenomena."

Early in her career neuroscientist Allyson Mackey began thinking about molars. As a researcher who studies brain development, she wanted to know whether when these teeth arrived might indicate early maturation in children.

"I've long been concerned that if kids grow up too fast, their brains will mature too fast and will lose plasticity at an earlier age. Then they'll go into school and have trouble learning at the same rate as their peers," says Mackey, an assistant professor in the Department of Psychology at Penn. "Of course, not every kid who experiences stress or [is] low income will show this pattern of accelerated development."

What would help, she thought, was a scalable, objective way—a physical manifestation, of sorts—to indicate how children embodied and responded to stresses in their world. Eruption timing of the first permanent molars proved to be just that.

In the Proceedings of the National Academy of Sciences, Mackey, with doctoral student Cassidy McDermott and colleagues from Penn's School of Dental Medicine and the University of Missouri-Kansas City, shows that children from lower-income backgrounds and those who go through greater adverse childhood experiences get their first permanent molars earlier. The findings, generated initially from a small study and replicated using a nationally representative dataset, align with a broader pattern of accelerated development often seen under conditions of early-life stress.

"It's really important for us to understand how to detect early maturation sooner," Mackey says. "Right now, we're relying on seeing when kids hit puberty, which might be too late for some meaningful interventions. If we can inexpensively see that a child is experiencing this maturation earlier, we might be able to direct more intervention resources toward them."

A novel rating system

Broadly speaking, Mackey's lab studies how the brain changes and grows as people learn. It's well-established that stress during childhood speeds up maturation and that children who hit puberty earlier are at greater risk for both physical and mental health problems in adulthood.

Beyond that, in studies across primate species, molar eruption has been used to measure childhood length and correlates with a number of other developmental events. Similarly, for humans, the timing of dental events often plays a role in estimating biological age.

"That all made molar eruption a compelling developmental indicator," says McDermott, who is training to be a clinical psychologist.

It helped that more than 100 children, ages 4 to 7, had been participating in two Penn brain development studies, which included structural and functional MRI scans. "There's one type of MRI scan called a T2 weighted scan where you can visualize the morphology of the tooth pretty well," McDermott says. These scans—typically used to look at the brain—showed the researchers just how close these molars were to breaking through the gum line.

Once Mackey and McDermott realized this, they partnered with Katherine Hilton, then a student in Penn Dental Medicine, and Muralidhar Mupparapu, a professor in the Department of Oral Medicine, who developed a novel scale to precisely rate each tooth's position.

"The scale ranges from 1 to 4," McDermott says. "At the low end of the scale is 1, which is before the tooth has really developed at all. As the tooth emerges, there are intermediate stages, and the highest rating, a 4, is when the tooth is fully in the mouth and parallel with the other teeth." Four molars each received a score, which then got averaged, leaving a single score per individual.

Controlling for factors like age and gender, the researchers then looked for associations between early environment and molar eruption. "What we found is that income and adverse childhood experiences are both individually associated with molar eruptions status," McDermott says.

Replicating the findings

Those findings derived from just 117 participants, so although the correlation was clear, Mackey and McDermott hoped to replicate what they'd seen.

Collaborators at the University of Missouri-Kansas City told them about a large population-representative dataset called the National Health and Nutrition Examination Survey (NHANES), which is publicly available and includes dental data, demographic data, and family income, among other measures.

"Because our sample is only from one city and is much smaller than a population-representative study like that," McDermott says, "we saw it as an opportunity to verify that the findings exist outside of what we had collected in Philadelphia."

Though some facets differed—NHANES measures dental development a little differently, for example—the models showed similar results, indicating a connection between lower family income and earlier first molars.

Whether this overall trend is new or just now coming to light is something Mackey wants to study further. She's also curious about when the rate of maturation gets set. "Is it as early as in utero or is it dynamically adjusted based on stressors in the world?" she says. "If it's the latter, that tells you there are more opportunities to intervene."

Present implications, future work

There are still significant unknowns, as well as findings that need further examination, Mackey says. For example, the research team found racial disparities in this timing, with first molars emerging in Black children sooner than in white children.

"These race differences in molar eruption have been known for a long time, but no one thought critically about where they came from," she says. "It's consistent with higher levels of stress due to structural racism. This is a clear indication that it's not just speculation that experiences with racism can cause stress and early aging. They are having an effect on kids that we can't ignore."

For all children, a year-plus of pandemic-driven grief and social isolation most certainly amplified stress levels, making it even more important to understand who is at greatest risk for early maturation, Mackey says.

Yet she and McDermott emphasize that molar timing shouldn't become another parental fear. "What I really don't want is for parents to either worry or feel complacent just based on when their kids got their molars," says Mackey. "We don't have those data yet."

The Penn researchers are working on it. In the future, they hope to collaborate with dental offices to recruit children into studies based on their molar-eruption status. The goal would be to follow them into adulthood, to get more information on what precisely early first molars may indicate. "If this is the meaningful discovery that I think it is," Mackey says, "I would love for many scientists to jump on board and test these hypotheses."

Even the best face masks work only as well as their fit.

And poorly fitting face masks greatly increase the risk of infection from airborne pathogens compared to custom-fitted masks, according to a new study by the University of Cincinnati.

Researchers in UC's College of Engineering and Applied Science used computerized tomography or CT scans of three different-sized face masks attached to three different-sized dummy heads to measure the gaps between the face and the fabric. Then they calculated the leaks from these gaps to determine the infection risk. 

They found that while N95 masks are effective barriers against airborne diseases like COVID-19, poorly fitting masks can have substantial leaks around the face that reduce their effectiveness and increase the risk of infection.

"Many people do not realize that the fit of face masks can vary. There are different face shapes and different sizes of masks," said Rupak Banerjee, a professor in UC's Department of Mechanical and Materials Engineering.

"If you do not match them well, you can lead to greater leaks and higher risks of infection," he said.

The study was published in the Nature journal Scientific Reports.

Banerjee collaborated on the study with his former students, including UC graduates Prasanna Hariharan, Neha Sharma and Gavin D'Souza. Hariharan, the study's lead author, works for the U.S. Food and Drug Administration's Division of Applied Mechanics.

UC's use of CT scans improved the accuracy of contact modeling from previous studies that relied on gap geometry and computational models for estimates.

UC used three different sized N95 face masks from the National Institute for Occupational Safety and Health along with three standard mannequin heads identified as small, medium and large. From the CT scans, they could create a 3D computer-aided design model that showed the gaps between the masks and the face on each subject.

They calculated the airflow rates through the gaps to identify the relative infection risk for each mask on each face.

The aerosol transport attributed to leaking out the sides of the masks varied from as little as 30% to as much as 95% for the worst-fitting masks. Researchers found the leaks were most likely around the nose. Interestingly, they noticed that the gaps were often asymmetrical on the symmetrical dummy faces. 

Researchers found that poorly fitted face masks can as much as double the infection risk to the wearers and people around them.

"A lot of people don't wear masks properly. They keep the nose exposed, which isn't helpful," Banerjee said.

But understanding that masks can often leak around the nose could help people pay more attention to the fit when buying and wearing masks.

Editor of the American Society of Mechanical Engineering Journal of Medical Devices, Banerjee said innovations in infection control have been hot topics this year.

"We are going to have a special issue soon about pandemic-response medical devices, including face masks and face shields," he said.

Meanwhile, UC's research could educate consumers and help manufacturers design better-fitting masks, he said.

While many countries are relaxing social-distancing mandates, Banerjee said he isn't putting his face masks away just yet.

"I'll continue to wear a face mask because of the risk from the COVID-19 variants," he said. "We're still not sure how effective the vaccine is on the variants. So it's a good idea to continue wearing masks in gatherings for now."

DARIEN, IL - A study of NCAA Division I college football games found a significant association between the performance of away teams and both their direction of travel and the time of day when games were played.

Results show that away teams playing in the afternoon allowed 5% more points and forced 13% more opponent turnovers than those playing in the evening. Teams traveling eastward to play on the road threw 39% more interceptions than those traveling in the same time zone. There also was a significant interaction between direction of travel and time of day for points allowed, and a marginal interaction for points scored.

"Most notably, we found that teams playing in the afternoon actually allowed more points and forced more opponent turnovers than teams playing in the evening," said faculty advisor Sean Pradhan, who has a doctorate in sport management and is an assistant professor of sports management and business analytics in the School of Business Administration at Menlo College in Atherton, California. "Our results also showed that teams traveling eastward threw more interceptions than teams traveling in the same time zone."

Pradhan and co-investigator Micah Kealaiki-Sales analyzed data from 1,909 NCAA Division I college football games played by 64 "Power Five" conference teams during the 2014 to 2019 regular seasons (i.e., the College Football Playoff Era). All games played at neutral sites were excluded. Data were collected from the publicly available sports database, Sports-Reference. The researchers controlled for both visiting and home team conference, day of game, and team rankings.

According to Pradhan and Kealaiki-Sales, the findings offer novel evidence for the influence of circadian factors on the performance of collegiate athletes.

"Much of the past research on travel and sports performance has focused on professional teams," noted Pradhan. "Our study extends the literature by providing an examination of NCAA Division I college football teams, where research on the effects of travel has been relatively limited and findings have been inconsistent. Given that the level of student-athlete support naturally varies across colleges, our results do highlight the impact of certain factors in travel for coaches, staff, and even student-athletes to consider."

The research abstract was published recently in an online supplement of the journal Sleep and will be presented as poster from June 9 - Nov. 30 during Virtual SLEEP 2021. SLEEP is the annual meeting of the Associated Professional Sleep Societies, a joint venture of the American Academy of Sleep Medicine and the Sleep Research Society.