Culture

For engineers developing new materials or protective coatings, there are billions of different possibilities to sort through. Lab tests or even detailed computer simulations to determine their exact properties, such as toughness, can take hours, days, or more for each variation. Now, a new artificial intelligence-based approach developed at MIT could reduce that to a matter of milliseconds, making it practical to screen vast arrays of candidate materials.

The system, which MIT researchers hope could be used to develop stronger protective coatings or structural materials -- for example, to protect aircraft or spacecraft from impacts -- is described in a paper in the journal Matter, by MIT postdoc Chi-Hua Yu, civil and environmental engineering professor and department head Markus J. Buehler, and Yu-Chuan Hsu at the National Taiwan University.

The focus of this work was on predicting the way a material would break or fracture, by analyzing the propagation of cracks through the material's molecular structure. Buehler and his colleagues have spent many years studying fractures and other failure modes in great detail, since understanding failure processes is key to developing robust, reliable materials. "One of the specialties of my lab is to use what we call molecular dynamics simulations, or basically atom-by-atom simulations" of such processes, Buehler says.

These simulations provide a chemically accurate description of how fracturing happens, he says. But it's slow, because it requires solving equations of motion for every single atom. "It takes a lot of time to simulate these processes," he says. The team decided to explore ways of streamlining that process, using a machine-learning system.

"We're kind of taking a detour," he says. "We've been asking, what if you had just the observation of how fracturing happens [in a given material], and let computers learn this relationship itself?" To do that, artificial intelligence (AI) systems need a variety of examples to use as a training set, to learn about the correlations between the material's characteristics and its performance.

In this case, they were looking at a variety of composite, layered coatings made of crystalline materials. The variables included the composition of the layers and the relative orientations of their orderly crystal structures, and the way those materials each responded to fracturing, based on the molecular dynamics simulations. "We basically simulate, atom by atom, how materials break, and we record that information," Buehler says.

They painstakingly generated hundreds of such simulations, with a wide variety of structures, and subjected each one to many different simulated fractures. Then they fed large amounts of data about all these simulations into their AI system, to see if it could discover the underlying physical principles and predict the performance of a new material that was not part of the training set.

And it did. "That's the really exciting thing," Buehler says, "because the computer simulation through AI can do what normally takes a very long time using molecular dynamics, or using finite element simulations, which are another way that engineers solve this problem, and it's very slow as well. So, this is a whole new way of simulating how materials fail."

How materials fail is crucial information for any engineering project, Buehler emphasizes. Materials failures such as fractures are "one of the biggest reasons for losses in any industry. For inspecting planes or trains or cars, or for roads or infrastructure, or concrete, or steel corrosion, or to understand the fracture of biological tissues such as bone, the ability to simulate fracturing with AI, and doing that quickly and very efficiently, is a real game changer."

The improvement in speed produced by using this method is remarkable. Hsu explains that "for single simulations in molecular dynamics, it has taken several hours to run the simulations, but in this artificial intelligence prediction, it only takes 10 milliseconds to go through all the predictions from the patterns, and show how a crack forms step by step."

The method they developed is quite generalizable, Buehler says. "Even though in our paper we only applied it to one material with different crystal orientations, you can apply this methodology to much more complex materials." And while they used data from atomistic simulations, the system could also be used to make predictions on the basis of experimental data such as images of a material undergoing fracturing.

"If we had a new material that we've never simulated before," he says, "if we have a lot of images of the fracturing process, we can feed that data into the machine-learning model as well." Whatever the input, simulated or experimental, the AI system essentially goes through the evolving process frame by frame, noting how each image differs from the one before in order to learn the underlying dynamics.

For example, as researchers make use of the new facilities in MIT.nano, the Institute's facility dedicated to fabricating and testing materials at the nanoscale, vast amounts of new data about a variety of synthesized materials will be generated.

"As we have more and more high-throughput experimental techniques that can produce a lot of images very quickly, in an automated way, these kind of data sources can immediately be fed into the machine-learning model," Buehler says. "We really think that the future will be one where we have a lot more integration between experiment and simulation, much more than we have in the past."

The system could be applied not just to fracturing, as the team did in this initial demonstration, but to a wide variety of processes unfolding over time, he says, such as diffusion of one material into another, or corrosion processes. "Anytime where you have evolutions of physical fields, and we want to know how these fields evolve as a function of the microstructure," he says, this method could be a boon.

CAMBRIDGE, MA -- MIT scientists have identified a potential new strategy for treating Fragile X syndrome, a disorder that is the leading heritable cause of intellectual disability and autism.

In a study of mice, the researchers showed that inhibiting an enzyme called GSK3 alpha reversed many of the behavioral and cellular features of Fragile X. The small-molecule compound has been licensed for further development and possible human clinical trials.

From the mouse studies, there are signs that this compound may not have the same limitations of another class of Fragile X drugs that failed in human clinical trials a few years ago, says Mark Bear, the Picower Professor of Neuroscience, a member of MIT's Picower Institute for Learning and Memory, and one of the senior authors of the study.

GSK3 inhibitors might also be useful against other diseases in which GSK3 plays a role, including Alzheimer's disease, he says.

Florence Wagner, director of medicinal chemistry at the Broad Institute's Stanley Center for Psychiatric Research, is also a senior author of the study, which appears today in Science Translational Medicine. The lead authors are MIT postdoc Patrick McCamphill, former MIT graduate student Laura Stoppel, and former MIT postdoc Rebecca Senter.

Many targets

Fragile X affects about 1 in 2,500 to 4,000 boys and 1 in 7,000 to 8,000 girls, and is caused by a genetic mutation of a protein called Fragile X mental retardation protein (FMRP). In addition to intellectual disability, symptoms include epilepsy, attention deficit and hyperactivity, hypersensitivity to noise and light, and autistic behaviors such as hand-flapping.

Bear's lab, which has been studying Fragile X for about two decades, has previously shown that protein synthesis at synapses, the specialized junctions between neurons, is stimulated by a neurotransmitter receptor called metabotropic glutamate receptor 5 (mGluR5). FMRP normally regulates this protein synthesis. When FMRP is lost, mGluR5-stimulated protein synthesis becomes overactive, and this can account for many of the varied symptoms seen in Fragile X.

In studies of mice, Bear and others have found that compounds that inhibit the mGluR5 receptor could reverse most of the symptoms of Fragile X. However, none of the mGluR5 inhibitors that have been tested in clinical trials have succeeded.

In the meantime, the MIT team, along with many other research groups, has been searching for other molecules that could be targeted to treat Fragile X.

"We and many other labs have been chipping away at this and trying to understand the key molecular players. There's quite a large number now, and there have been different manipulations in the signaling pathway that can correct Fragile X phenotypes in animals," Bear says. "We like to refer to this as a target-rich environment. If at first you don't succeed therapeutically, you have many other shots on goal."

Some studies suggested that GSK3 was overactive in Fragile X mouse models and that this activity could be turned down using lithium. However, the required dosage of lithium has adverse side effects in children. Pharmaceutical companies developed other small-molecule drugs that inhibit GSK3, but these triggered an accumulation of a protein called beta-catenin, which can lead to cancerous cell proliferation.

The GSK3 enzyme comes in two forms, alpha and beta, so Wagner, along with Edward Holson, former director of medicinal chemistry at the Stanley Center, and Edward Scolnick, chief scientist emeritus at the Stanley Center, set out to develop drugs that would inhibit either one or the other.

"Studies had been published showing that if you selectively knock out either alpha or beta, it wouldn't trigger beta-catenin accumulation," Wagner says. "GSK3 inhibitors had been tested in Fragile X models before, but it's never gone anywhere because of the toxicity issue."

After a screen of more than 400,000 drug compounds, Wagner identified a handful that inhibited both forms of GSK3. By slightly altering their structures, she then came up with versions that could target selectively the alpha or beta forms.

Bear's lab tested the selective inhibitors in genetically engineered mice that lack the FMRP protein, and found that the inhibitor specific to GSK3 alpha eliminated one of the common Fragile X symptoms -- seizures induced by loud tones. Following that, they found that the GSK3 alpha inhibitor also successfully reversed several other symptoms of Fragile X, while the GSK3 beta inhibitor did not.

These symptoms include overproduction of protein as well as altered synaptic plasticity, impairment of some types of learning and memory, and hyperexcitability of some neurons.

"It checked off all the boxes that we would have expected from inhibiting mGluR5 or the signaling pathway downstream," Bear says. "It's really amazing that if you can correct the excess protein synthesis with a drug compound, a dozen other phenotypes are going to be corrected."

Exploring side effects

GSK3 is a kinase, which means that it controls other proteins by adding chemical groups called phosphates to them, but its exact role in Fragile X is not yet known. In this study, the researchers found that GSK3 is part of the same signaling pathway controlled by mGluR5, but GSK3 appears to act later in the pathway.

The initial findings in mice suggest that GSK3 alpha inhibitors do not have some of the complications that may have caused the mGluR5 inhibitors to fail in clinical trials, Bear says. In those trials, mGluR5 inhibitors were found to cause hallucinations in some people, which limits the dose that can be given. (In mice, hallucinations cannot be directly measured, but there are techniques for indirectly testing hallucinogenic potential.) Mouse studies of mGluR5 inhibitors did show that potential for causing hallucination, but studies of GSK3 alpha inhibitors have not shown it.

Another side effect seen in mouse studies of mGluR5 inhibitors is the development of resistance to long-term treatment, for some of the symptoms of the disorder.

"We don't know whether the mGluR trials failed because of treatment resistance, but it's a viable hypothesis," Bear says. "What we do know is with the GSK3 alpha inhibitor, we do not see that in mice, to the extent that we've looked at it."

GSK3 inhibitors may also hold promise for treating other diseases in which GSK3 plays a role. In a Science Translational Medicine study published last year, also co-authored by Wagner, researchers at the Broad Institute and Dana-Farber Cancer Institute showed that selective GSK3 inhibitors could be effective against acute myeloid leukemia.

GSK3 could also be a potential target for Alzheimer's treatment, as it is responsible for phosphorylating Tau, a protein that forms tangles in the brains of Alzheimer's patients.

What The Study Did: Researchers looked at whether patients with nonfatal intentional opioid overdoses would be more likely to die by suicide than patients with unintentional overdoses with an analysis of deaths following nonfatal opioid overdoses of intentional, unintentional and undetermined intent in California from 2009 to 2011.

Authors: Mark Olfson, M.D., M.P.H., of Columbia University in New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamapsychiatry.2020.1045)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

What The Study Did: This randomized clinical trial investigated the association between pro-male gender bias and negative stereotypes against women during surgical residency on surgical skills and proactive career development of residents in general surgery training programs. Factors contributing to the underrepresentation of women in surgery aren't completely understood.

Authors: Sara P. Myers, M.D., Ph.D., of the University of Pittsburgh School of Medicine, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamasurg.2020.1127)

Editor's Note: The article includes conflict of interest and funding/support disclosures. Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

Low-carb, high-fat ketogenic diets, which have attracted public interest in recent years for their proposed benefits in lowering inflammation and promoting weight loss and heart health, have a dramatic impact on the microbes residing in the human gut, collectively referred to as the microbiome, according to a new UC San Francisco study of a small cohort of volunteer subjects. Additional research in mice showed that so-called "ketone bodies," a molecular byproduct that gives the ketogenic diet its name, directly impact the gut microbiome in ways that may ultimately suppress inflammation, suggesting evidence for potential benefits of ketone bodies as a therapy for autoimmune disorders affecting the gut.

In ketogenic diets, carbohydrate consumption is dramatically reduced in order to force the body to alter its metabolism to using fat molecules, rather than carbohydrates, as its primary energy source -- producing ketone bodies as a byproduct -- a shift that proponents claim has numerous health benefits.

"I got interested in this question because our prior research showed that high-fat diets induce shifts in the gut microbiome that promote metabolic and other diseases in mice, yet ketogenic diets, which are even higher in fat content, have been proposed as a way to prevent or even treat disease," said Peter Turnbaugh, PhD, a UCSF associate professor of microbiology and immunology, member of the UCSF Benioff Center for Microbiome Medicine and a Chan Zuckerberg Biohub Investigator. "We decided to explore that puzzling dichotomy."

In their new study, published May 20, 2020, in Cell, Turnbaugh and colleagues partnered with the nonprofit Nutrition Science Initiative to recruit 17 adult overweight or obese nondiabetic men to spend two months as inpatients in a metabolic ward where their diets and exercise levels were carefully monitored and controlled.

For the first four weeks of the study, the participants were given either a "standard" diet consisting of 50 percent carbs, 15 percent protein and 35 percent fat, or a ketogenic diet comprising 5 percent carbs, 15 percent protein and 80 percent fat. After four weeks, the two groups switched diets, to allow the researchers to study how shifting between the two diets altered participants' microbiomes.

Analysis of microbial DNA found in participants' stool samples showed that shifting between standard and ketogenic diets dramatically changed the proportions of common gut microbial phyla Actinobacteria, Bacteroidetes, and Firmicutes in participants' guts, including significant changes in 19 different bacterial genera. The researchers focused in on a particular bacterial genus -- the common probiotic Bifidobacteria -- which showed the greatest decrease on the ketogenic diet.

To better understand how microbial shifts on the ketogenic diet might impact health, the researchers exposed the mouse gut to different components of microbiomes of humans adhering to ketogenic diets, and showed that these altered microbial populations specifically reduce the numbers of Th17 immune cells -- a type of T cell critical for fighting off infectious disease, but also known to promote inflammation in autoimmune diseases.

Follow-up diet experiments in mice, in which researchers gradually shifted animals' diets between low-fat, high-fat and low-carb ketogenic diets, confirmed that high-fat and ketogenic diets have opposite effects on the gut microbiome. These findings suggested that the microbiome responds differently as the level of fat in the animals' diet increases to levels that promote ketone body production in the absence of carbs.

The researchers observed that that as animals' diets were shifted from a standard diet towards stricter carbohydrate restriction, their microbes also began shifting, correlated with a gradual rise in ketone bodies.

"This was a little surprising to me," Turnbaugh said. "As someone who is new to the keto field, I had assumed that producing ketone bodies was an all-or-nothing effect once you got to a low enough level of carb intake. But this suggests that you may get some of the effects of ketosis quite quickly."

The researchers tested whether ketone bodies alone could drive the shifts they had seen in the gut's microbial ecosystem by directly feeding ketone bodies to mice. They found that even in mice who were eating normal amounts of carbohydrates, the mere presence of added ketones was enough to produce many of the specific microbial changes seen in the ketogenic diet.

"This is a really fascinating finding because it suggests that the effects of ketogenic diets on the microbiome are not just about the diet itself, but how the diet alters the body's metabolism, which then has downstream effects on the microbiome," Turnbaugh said. "For many people, maintaining a strict low-carbohydrate or ketogenic diet is extremely challenging, but if future studies find that there are health benefits from the microbial shifts caused by ketone bodies themselves, that could make for a much more palatable therapeutic approach."

What The Study Did: This observational study looked at the disparities that exist between women and men waiting to receive a liver transplant, such as being more likely to die while on the wait list, and how much these differences are associated with factors including geographic location, medical urgency and liver size.

Authors: Jayme E. Locke, M.D., M.P.H., of the University of Alabama at Birmingham, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamasurg.2020.1129)

Editor's Note: The article includes conflict of interest disclosures. Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

May 20, 2020 -- When things get rough, many Americans turn to prescription pills. About one in eight over the age of 12 take antidepressants for mental disorders such as depression and anxiety, and a quarter of those have done so for 10 years or more, according to a 2017 study by the National Center for Health Statistics. And the use of antidepressants increased 65% from 1999 to 2014.

But University of Utah biomedical engineering assistant professor Jan Kubanek has discovered that treatments of brain disorders may not have to require drugs or invasive surgery at all - just sound waves.

In a new paper published Wednesday, May 20, in the journal Science Advances, Kubanek describes a procedure in which sound waves of high frequency (ultrasound) can be emitted into a patient's brain to alter his or her state. It's a non-invasive treatment that doesn't involve medications or surgery and has a unique potential to treat mental disorders including depression and anxiety and neurological disorders such as chronic pain and epilepsy. The paper can be viewed at https://advances.sciencemag.org/content/6/21/eaaz4193.

"Brain disorders should be treated in targeted and personalized ways instead of offering patients cocktails of drugs," says Kubanek. "But to do that, we need a tool that provides noninvasive, precise, and personalized treatments to address the source of the problem in each individual. This up until now has only been a dream."

The idea of using ultrasonic waves for such precision therapy involves pulses of sound at a high, inaudible frequency aimed into the brain using an ultrasonic transducer, similar to wands used for ultrasound scans. The sound pulses target neural circuits in the brain and cause neuronal membranes to oscillate, thus activating neurons and influencing the behavior those neurons control. There is no pain or discomfort, and there is no surgical technique involved.

"This way, you can change the activity of the neurons and also the connectivity between the stimulated neurons and their neighbors, which has the potential to return malfunctioning neural circuits back to their normal state," Kubanek says.

The team delivered ultrasonic waves into the brain of monkeys deciding whether to look left or right. With the right frequencies and targeting the right neurons, the researchers were able to control whether the subjects chose right or left. The animals did not feel the ultrasound during the procedure.

Kubanek says that this experiment provided a simple way to measure how potent the effects of ultrasound are. "The paper shows that ultrasound can produce strong effects, up to the point of influencing behavior. And changes in behavior is what we ultimately care about. For instance, we may be able to correct poor decision-making or at least reduce a person's tremor in the hand." he says.

Patients who don't respond to drugs are currently treated with other neuromodulation methods that are either invasive or lack good targeting. Kubanek said that ultrasonic waves do not have those drawbacks. A clinical team can treat a patient systematically until it identifies the target that shows the most dramatic improvement in the person's symptoms. Researchers used short stimuli -- at most 40 seconds -- but even such short stimuli can rewire the target circuits for hours. Kubanek believes longer stimuli of durations close to 40 minutes could produce results that potentially last for weeks.

Kubanek says his team has built a prototype device to perform these treatments in patients. He plans to begin first clinical trials in patients with major depression in three years.

Most biological processes are carried out by complexes of multiple proteins that work together to carry out some function. How these complicated structures could have evolved is one of modern biology's great puzzles, because they generally stick together using elaborate molecular interfaces, and the intermediate forms through which they came into being have been lost without a trace.

Now an international team of researchers led by University of Chicago Professor Joseph Thornton, PhD, and graduate student Arvind Pillai has revealed that complexity can evolve through surprisingly simple mechanisms. The group identified the evolutionary "missing link" through which hemoglobin -- the essential four-part protein complex that transports oxygen in the blood of virtually all vertebrate animals -- evolved from simple precursors. And they found that it took just two mutations more than 400 million years ago to trigger the emergence of modern hemoglobin's structure and function.

The study, "Origin of complexity in haemoglobin evolution," will be published online in the journal Nature on May 20. The team also includes scientists at Texas A&M University, University of Nebraska-Lincoln, and Oxford University (UK).

Each hemoglobin molecule is a four-part protein complex made up of two copies each of two different proteins, but the proteins to which they are most closely related do not form complexes at all. The team's strategy, pioneered in Thornton's lab over the last two decades, was a kind of molecular time travel: use statistical and biochemical methods to reconstruct and experimentally characterize ancient proteins before, during and after the evolution of the earliest forms of hemoglobin. This allowed them to identify the missing link during hemoglobin evolution - a two-part complex, consisting of two copies of a single protein, which existed before the last common ancestor of humans and sharks. This ancient two-part complex did not yet possess any of modern hemoglobin's critical properties that allow it to bind oxygen in the lungs and deliver it to distant cells in the brain, muscles and other tissues.

By introducing into this missing link protein various mutations that occurred during the next historical interval, they found that just two mutations on the protein's surface triggered formation of the four-part complex and imparted the critical changes in its oxygen-binding function.

The traditional view of the evolution of biological complexity -- first proposed by Charles Darwin and elaborated recently by Richard Dawkins -- is that complexity increases gradually through a long journey of many mutations, each of which is favored by natural selection because it causes small improvements in function and fitness. The new research shows that, at the molecular level at least, new complex forms can be brought into being very quickly.

"We were blown away when we saw that such a simple mechanism could confer such complex properties," Thornton said. "This suggests that jumps in complexity can happen suddenly and even by chance during evolution, producing new molecular entities that eventually become essential to our biology."

The project began when Pillai, a graduate student in the Department of Ecology and Evolution, approached Thornton and Georg Hochberg, PhD, a postdoctoral scholar in his laboratory, with the idea that hemoglobin could be a test case to see how complex molecules evolved throughout history.

"Hemoglobin's structure and function has been studied more than perhaps any other molecule," said Pillai. "But nothing was known about how it originated during evolution. It's a great model because hemoglobin's components are part of a larger protein family in which the closest relatives don't form complexes but function in isolation. Their history can be reconstructed from the sequences of its modern descendants, and there are great laboratory tools for characterizing their properties."

Thornton said that Pillai's idea was "brilliant, and it inspired a massive amount of experimental work by Arvind and the rest of the team." Speculation about how hemoglobin might have evolved goes back at least 60 years to Linus Pauling and Max Perutz, the founding fathers of protein biochemistry, but until now there was no way to study the problem experimentally.

Analysis of the ancient proteins' atomic structures showed how the two mutations took advantage of even more ancient features to assemble the intermediate two-part complex into the four-part complex. The mutations introduced two changes on the protein surface that allowed it to bind tightly to the surface of the other protein, which remained unchanged as it was recruited into the new interaction. Other ancient parts of the two surfaces also stuck together simply by chance, adding further strength to the interaction that was triggered by the two new mutations. Those older elements, Thornton pointed out, and even the two-part complex itself, must have existed then by chance, rather than because they enhanced the protein's final structure or function, because they evolved before those properties came into being.

Perhaps the most surprising result was that the two critical mutations, by inducing formation of the four-part structure, also triggered the critical changes in the complex's oxygen-binding functions. Hemoglobin can perform its physiological function because its affinity for oxygen is high enough to bind oxygen in the lungs, but low enough to release it in the tissues elsewhere in the body. It also binds oxygen cooperatively: When one of the four components takes up a molecule of oxygen, the other components tend to do the same - and this happens in the reverse direction, as well -- so the whole complex becomes even more effective at recruiting oxygen and releasing it in the right places.

Hemoglobin's ancient precursors - including the missing link two-part complex - bound oxygen too tightly and were not cooperative, so they could not have effectively performed the oxygen-exchange function. The researchers found that the two key mutations not only conferred the four-part structure but also imparted hemoglobin's critical oxygen-binding properties. Although the mutations are on the part of the protein's surface that assemble the complex together - not at its oxygen-binding site - the two regions are connected by an ancient string of amino acids found in all members of the globin protein family. When the four-part complex assembles, this string moves, and the oxygen-binding site is reshaped in a way that makes it bind oxygen more loosely. And when one component of the hemoglobin complex does bind oxygen, the string moves back, reshaping the surface that binds the neighboring proteins together, which allows the neighbor to get better at binding oxygen, too. In this way, complex functional properties appeared as an immediate side effect when hemoglobin's ability to assemble first evolved.

"Imagine if those two mutations never occurred, or if the structural features that they took advantage of weren't in place at the time," Thornton said. "Hemoglobin as we know it would not have evolved, and neither would many of the subsequent innovations that depend on efficient oxygen transport, like rapid metabolism and the ability to grow much larger and move much faster than our ancient marine ancestors."

The study will be released on May 20, 2020, on the Nature website and on May 28 in the journal's print issue. Co-authors along with Pillai, Hochberg and Thornton include University of Chicago graduate student Carlos Cortez-Romero, Yang Liu and Arthur Laganowsky of Texas A&M University, Anthony Signore and Jay F. Storz of University of Nebraska-Lincoln, and Shane Chandler and Justin Benesch of Oxford University (UK).

Research into how the SARS-CoV-2 virus induces death is suggesting potential treatments for its most destructive complications.

Leading immunologists in Japan are proposing a possible molecular mechanism that causes massive release of proinflammatory cytokines, or a cytokine storm, leading to the acute respiratory distress syndrome (ARDS) in COVID-19 patients. Their suggestions, published in the journal Immunity, are based on recent findings that explain how SARS-CoV-2 enters human cells.

ARDS is a life-threatening condition in which lungs become so inflamed and filled with fluid that they struggle to provide enough oxygen to the body. "To rescue the patients from this condition, it is vital to understand how SARS-CoV-2 triggers the cytokine storm, that leads to ARDS," explains Masaaki Murakami, the head of immunology laboratory at Hokkaido University's Institute for Genetic Medicine.

Murakami, together with his collaborator Toshio Hirano from the National Institutes for Quantum and Radiological Science and Technology, reviewed two recent studies by Zhou et al. and Hoffmann et al. in order to understand their implications for finding effective therapeutic strategies for ARDS in COVID-19 patients.

Together, the studies suggest that SARS-CoV-2 enters human cells by attaching to a cell surface receptor called ACE2 and utilizing a human enzyme called TMPRSS2. "Drugs that block the ACE2 receptor or that inhibit the enzyme could help treat the initial stages of the disease," says Murakami. "However, ARDS with cytokine storm starts to appear in the later phase of infection even when the number of virus decreases. So, there must be another pathway that causes the cytokine storm."

SARS-CoV-2 is known to be engulfed into the human cell along with the ACE2 receptor it had combined with. "This reduces the number of ACE2 receptors on cells, leading to an increase of a polypeptide, called angiotensin II, in the blood," says Murakami. Angiotensin II triggers an inflammatory pathway involving NF-κB and IL-6-STAT3 particularly in nonimmune cells including endothelial cells and epithelial cells. "This pathway forms a positive feedback cycle, named IL-6 amplifier, resulting in its excessive activation and therefore the cytokine storm and ARDS," says Hirano, a pioneer in IL-6 research.

"Part of this pathway involving NF-κB or IL-6-STAT3, or the both, is enhanced with age, which could be why older people are more at-risk of death following COVID-19 infection compared to other age groups," explains Murakami. "Targeting these pathways, such as with the anti-IL-6 receptor antibody called tocilizumab, could disrupt this life-threatening inflammatory reaction in COVID-19 patients," Hirano added.

Have pollen. Must travel.

Over 80% of the world's flowering plants must reproduce in order to produce new flowers, according to the U.S. Forest Service. This process involves the transfer of pollen between plants by wind, water or insects called pollinators -- including bumblebees.

In a new study, researchers at the University of Missouri discovered spiny pollen -- from a native wild dandelion species in the southern Rocky Mountains -- has evolved to attach to traveling bumblebees. Using a highly detailed electron scanning microscope, the research team could observe the microscopic surface of the spiny pollen, which otherwise looks like yellow dust to the naked eye.

"We observed this native pollen from the Rockies has optimally spaced spines that allow it to easily attach to a pollinator, such as a bumblebee," said Austin Lynn, a recent graduate with a doctorate in biology from the Division of Biological Sciences in the College of Arts and Science. "When we compared that with the average lawn dandelion, which does not need pollen to reproduce, we saw that the pollen on the lawn dandelion has a shorter distance between these spines, making it harder to attach to traveling pollinators. Therefore, we show this wild dandelion pollen has evolved over many generations to create an optimal shape for attaching to pollinators."

Previous studies have examined spiny pollen, but this is one of the first studies focusing on the pollen's spines. Lynn, the lead researcher on the study, said the researchers were also able to refute a competing idea that spiny pollen serves as a defensive mechanism to protect the pollen from being eaten.

"The spiny pollen actually acts like Velcro," Lynn said. "So, when bees are harvesting pollen for food, this pollen is sticking to their hair. It's a great example of mutualism where the plant needs the pollinator to reproduce and the pollinator needs the plant for its food."

The researchers plan to study how a bumblebee's hairs contribute to this process.

The study, "Sexual and natural selection of pollen morphology in Taraxacum," was published in the American Journal of Botany. Other authors on the study include Emelyn Piotter and Candace Galen at MU; and Ellie Harrison at Colorado State University. Funding was provided by the Mountain Area Land Trust and a Cherng Foundation Scholarship. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

'Orthonectida is a group of parasitic creatures that was discovered long ago - in 1877. However, their position in the animal system until recently remained a mystery,' said George Slyusarev, Professor at St Petersburg University and Doctor of Biology. 'Initially, they were considered extremely primitive animals that occupy an intermediate position between Protozoans and Metazoans. Hence, their old name is "mesozoa": from the Greek "meso" - "between" animals and protists. However, when we began to research them, they turned out to be not that simple.'

The idea of sequencing the genome of the smallest orthonectid came to the scientists from St Petersburg University in 2016 when they were carrying out another investigation. They were deciphering a genome of another species, a little larger, called Intoshia linei. At that time, it turned out to be one of the smallest genomes among metazoans. So, the researchers from St Petersburg suggested that the smaller Intoshia variabili might have even smaller genomes. Moreover, they could be compared and it would be possible to learn more about the evolution of these mysterious creatures.

The major challenge is whether the development of orthonectids corresponds to the basic tenets of the evolution of parasites, which over time not only become smaller and simpler morphologically, but also get rid of 'stuffer' fragments of the genome. To find this out, the scientists went to the University Marine Biological Station: it was here that Intoshia variabili was first discovered and described, which can also be found in the Barents Sea. It is quite difficult to grow these parasites in the laboratory, so biologists have to collect them in the field and in very small quantities. Then the samples are brought to St Petersburg, where molecular studies are carried out at the facilities of the Research Park of St Petersburg University.

"It turned out that the genome of the smallest representative of orthonectids that we sequenced contains the minimum number of genes that is ever possible for the normal functioning of a metazoan. At the moment, this is the smallest genome among all metazoans."

-Natalya Bondarenko, Candidate of Biology, Senior Research Associate, St Petersburg University

'Its size is 15.3 million base pairs. The number of genes is 5,120, and half of them are the so-called orphan genes, which do not group with any other genes known to science. They are unique to orthonectids. We continue to work in this direction to understand what these genes are and how they work in the genome,' said Natalya Bondarenko, Candidate of Biology and Senior Research Associate at St Petersburg University.

Moreover, the scientists from St Petersburg University were able to find genetic evidence that orthonectids belong to a specific type of animal - Annelida. Interestingly, as Natalya Bondarenko notes, among the annelids there were no real intraorganism parasites and orthonectids became a unique exception. Additionally, the biologists say that finding an organism with such a small genome is a great success, because it is convenient to use it as a model object for various studies.

'Ortonectids themselves are not as interesting as general biological issues related to the study of the evolution of parasitism in general: how does simplification occur in different groups of animals; how does it differ; and why do they come to the same thing in a variety of ways. The recent data makes it possible for us to move in any direction and study specifically, for example, the evolution of the nervous system and many other aspects,' explained Natalya Bondarenko.

We use cells to breathe, to moderate body temperature, to grow and many other every day processes, however the cells in these processes are so complex its left scientists perplexed into how they develop in different environments. Researchers from the University of Warwick say future research needs to look into the bioelectrical composition of cells for answers.

Cellular processes happen every day for survival, form homeostasis to photosynthesis and anaerobic respiration to aerobic respiration. However the complexity of cells has fascinated and challenged human understanding for centuries.

It's cellular "machinery" responsible for key functions have been the focus of biology research, and despite previous research exploring the molecular and genetic basis of these processes showing unprecedented insights, we still can't fully understand and predict cell behaviour when challenged to different conditions.Professor Orkun Soyer, School of Life Sciences, University of Warwick

In particular, the basis of heterogeneity in single-cell behaviour and the initiation of many different metabolic, transcriptional or mechanical responses to environmental stimuli remain largely unexplained.

Researchers from the School of Life Sciences at the University of Warwick have today, the 20th May had the paper 'Bioelectrical understanding and engineering of cell biology' published in the journal Royal Society Interface, in which they have gone beyond the status quo of understanding cell behaviours, and argue a combination of genetics, physics and physiology can be grounded on a bioelectrical conceptualisation of cells.

They argue that a bioelectrical view can provide predictive biological understanding, which can open up novel ways to control cell behaviours by electrical and electrochemical means, setting the stage for the emergence of bioelectrical engineering.

Dr Orkun Soyer, from the School of Life Sciences at the University of Warwick comments:

"When looking at the underlying chemistry of this "machinery" it is easy to recognise the importance of electricity in biological phenomena.

"Here we advocate that the understanding of cells as electrical entities will pave the way to fully understand, predict and modulate cellular function. When cellular functions are understood it could have a huge impact on healthcare, as conditions related to, for example, homeostasis such as heart failure or diabetes, could have new treatments researched if we can manipulate the bioelectricity in the cells."

Entrepreneurial motivation is important to economic growth because entrepreneurs create companies that produce new products and services, which in turn, boost productivity. But we know little about what motivates innovative entrepreneurs and how their motivations differ by gender, culture and other characteristics. A new study from researchers at Carnegie Mellon University and Columbia Business School sheds a light on the attributes that drive different types of entrepreneurs. By examining how entrepreneurs responded to motivation-related messages that involve money and social impact, the researchers concluded that women and people in altruistic cultures are more motivated by messages of social impact than by those related to money while men and people in less altruistic cultures are more motivated by messages related to money. The study was recently published in Management Science.

"Our results provide insights into the role of different motivations that affect the entrepreneurial process," explains Ananya Sen, assistant professor of information systems and economics at Carnegie Mellon University's Heinz College, who coauthored the study. "Understanding the impact of motivations can help firms identify and create strategies to develop competitive entrepreneurial advantage."

To determine what motivates entrepreneurs and how those motivations differ across gender and culture, researchers conducted three field experiments with the Inclusive Innovation Challenge (IIC) at the Massachusetts Institute of Technology, a global competition that helps entrepreneurs use technology to generate economic opportunity. MIT IIC is part of MIT Solve, a marketplace for social impact innovation with a mission to solve world challenges. The researchers surveyed nearly 15,000 entrepreneurs involved with the 2019 competition, as well as entrepreneurs from AngelList, a website for startups, investors, and job seekers, and from Dunn and Bradstreet, a company that provides commercial data and analysis for businesses.

Each individual was sent a randomly assigned social impact message (related to the possible social impact of IIC projects), a money message (related to the potential financial benefits of participating in the IIC), or a neutral message focused on technology (related to the possibility of winning the IIC). The researchers interpreted individuals' responses to the messages--from clicking on an email or website to learn more about the IIC competition to submitting applications for the competition--to determine their motivations.

The study found large and heterogeneous differences in the motivations of the respondents. Women responded more to the social impact message and less to the money message, while men responded the opposite way. The difference between the genders appeared to be driven more by their different responses to the social impact message than by their responses to the money message or the neutral message.

The study also found that people from more altruistic cultures--that is, those in which people act more prosocially, for example, in being more likely to donate to causes--were motivated more by the social impact message than by the money message. By contract, people from less altruistic cultures were motivated more by the money message.

The results were not driven by differences in the type of company the respondent worked for, its size, or other observable characteristics, but instead, appeared to come from differences in the underlying motivations of the entrepreneurs themselves, the study concluded.

"Our findings suggest that it's important to have a broader conceptualization of the motivations of innovative entrepreneurs that focuses on motivations beyond profit, and that accounts for fundamental dimensions of heterogeneity such as gender and culture," explains Jorge Guzman, assistant professor of management at Columbia Business School, who coauthored the study. "The results can inform interventions that foster innovative entrepreneurship policies and programs."

Springtime rains can be a surprising source of pollen.

University of Iowa researchers report that tree pollen fragments remain in the air for as many as 11 hours after heavy rains, and those granules can make their way deep into the lungs, potentially exacerbating allergies. The researchers base their findings on first-time direct measurements of pollen fragment concentrations during and after spring rains of varying severity in spring, 2019.

"Our results show that while pollen grains decrease substantially during rain, peak concentrations of submicron pollen fragments occur during rain events and then persist for several hours," says Elizabeth Stone, associate professor in the Department of Chemistry and corresponding author on the paper, published online in the journal Environmental Science & Technology Letters. "People who are sensitive to pollen in season should avoid going outdoors during rain events, especially thunderstorms, and for several hours afterward."

Pollen grains are pretty hardy, but they can rupture when subject to high humidity. This can happen during rains when a storm's updraft carries the grains to the cloud base, where humidity is quite high. The fragments then are shot back toward the surface by falling rain and the storm's downdraft.

The main difference between pollen and pollen fragments is, predictably, their size: Intact pollen grains are larger, at 20 to 100 microns, and settle to the ground. Pollen fragments, at less than 2.5 microns in size, do not settle readily and often remain aloft.

Stone and her team decided to test the results of previous research by directly measuring pollen from rain events in Iowa City, Iowa, between April 17 and May 31, 2019. This period of time, in prime tree pollen season, included light rains, thunderstorms, and even a severe weather event punctuated by a storm that spawned a tornado. In all, the researchers recorded rain on 28 days.

"Our study shows clearly that rain decreases intact pollen concentrations. But it can also increase pollen fragments," says Stone, who's also affiliated with the Department of Chemical and Biochemical Engineering at Iowa. "The interesting thing about the pollen fragments is the really high concentrations only last for a short period of time, primarily when it's raining and during the peak of the storm."

The researchers say pollen fragment concentrations remain elevated from 2.5 to 11 hours after a rain, the longer times associated with the heaviest rains.

Stone and her team measured the highest concentration of pollen fragments during a morning storm on May 18, with a peak concentration at 1.3 million pollen fragments per cubic meter of air. The next highest measured concentration was on May 24, with 960,000 pollen fragments per cubic meter of air.

"People who are susceptible or have allergies to pollen in season should consider rain events and especially thunderstorms to be a potential source of allergenic particles that could have negative respiratory impacts on them," Stone says. "My advice would be to stay indoors during and in the hours following rains and thunderstorms in the pollen season that they're allergic to."

AMES, Iowa - Moving more and sitting less was a challenge for many of us, even before states started issuing stay-at-home orders. Despite disruptions to our daily work and exercise routines, there are some subtle changes we can make at home to help improve our mental health.

New research, published by the American Journal of Preventive Medicine, found that substituting prolonged sedentary time with sleep was associated with lower stress, better mood and lower body mass index (BMI), and substituting light physical activity was associated with improved mood and lower BMI across the next year. Jacob Meyer, lead author and assistant professor of kinesiology at Iowa State University, says light activity can include walking around your home office while talking on the phone or standing while preparing dinner.

"People may not even think about some of these activities as physical activity," Meyer said. "Light activity is much lower intensity than going to the gym or walking to work, but taking these steps to break up long periods of sitting may have an impact."

Meyer and colleagues used data collected as part of the Energy Balance Study at the University of South Carolina. For 10 days, study participants, ranging in age from 21 to 35, wore an armband that tracked their energy expenditure. Meyer, director of the Wellbeing and Exercise Lab at Iowa State, says the data allowed researchers to objectively measure sleep, physical activity and sedentary time, rather than relying on self-reports.

In addition to the benefits of sleep and light physical activity, the researchers found moderate to vigorous activity was associated with lower body fat and BMI. Given the negative health effects of prolonged sedentary time, Meyer says the findings may encourage people to make small changes that are sustainable.

"It may be easier for people to change their behavior if they feel it's doable and doesn't require a major change," Meyer said. "Replacing sedentary time with housework or other light activities is something they may be able to do more consistently than going for an hour-long run."

Getting more sleep is another relatively simple change to make. Instead of staying up late watching TV, going to bed earlier and getting up at a consistent time provides multiple benefits and allows your body to recover, Meyer said. Sleeping is also unique in that it is time you're not engaging in other potentially problematic behaviors, such as eating junk food while sitting in front of a screen.

Something we can control

Making these subtle changes was associated with better current mood, but light physical activity also provided benefits for up to a year, the study found. While the research was conducted prior to the COVID-19 pandemic, Meyer says the results are timely given the growing mental health concerns during this time of physical distancing.

"With everything happening right now, this is one thing we can control or manage and it has the potential to help our mental health," Meyer said.

As states start to ease stay-at-home restrictions, Meyer is looking at changes in physical activity and sitting time with potentially interesting results for those who regularly worked out prior to the pandemic. Preliminary data from a separate study show a 32% reduction in physical activity. The question he and colleagues hope to answer is how current changes in activity interact with mental health and how our behaviors will continue to change over time.