Culture

Proteins are essential to the life of cells, carrying out complex tasks and catalyzing chemical reactions. Scientists and engineers have long sought to harness this power by designing artificial proteins that can perform new tasks, like treat disease, capture carbon, or harvest energy, but many of the processes designed to create such proteins are slow and complex, with a high failure rate.

In a breakthrough that could have implications across the healthcare, agriculture, and energy sectors, a team lead by researchers in the Pritzker School of Molecular Engineering (PME) at the University of Chicago has developed an artificial intelligence-led process that uses big data to design new proteins.

By developing machine-learning models that can review protein information culled from genome databases, the researchers found relatively simple design rules for building artificial proteins. When the team constructed these artificial proteins in the lab, they found that they performed chemistries so well that they rivaled those found in nature.

"We have all wondered how a simple process like evolution can lead to such a high-performance material as a protein," said Rama Ranganathan, Joseph Regenstein Professor in the Department of Biochemistry and Molecular Biology, Pritzker Molecular Engineering, and the College. "We found that genome data contains enormous amounts of information about the basic rules of protein structure and function, and now we've been able to bottle nature's rules to create proteins ourselves."

The results were published July 24 in the journal Science.

Using artificial intelligence to learn design rules

Proteins are made up of hundreds or thousands of amino acids, and these amino acid sequences specify the protein's structure and function. But understanding just how to build these sequences to create novel proteins has been challenging. Past work has resulted in methods that can specify structure, but function has been more elusive.

What Ranganathan and his collaborators realized over the past 15 years is that genome databases--which are growing exponentially--contain enormous amounts of information about the basic rules of protein structure and function. His group developed mathematical models based on this data and then began using machine-learning methods to reveal new information about proteins' basic design rules.

For this research, they studied the chorismate mutase family of metabolic enzymes, a type of protein that is important for life in many bacteria, fungi, and plants. Using machine-learning models, the researchers were able to reveal the simple design rules behind these proteins.

The model shows that just conservation at amino acid positions and correlations in the evolution of pairs of amino acids are sufficient to predict new artificial sequences that would have the properties of the protein family.

"We generally assume that to build something, you have to first deeply understand how it works," Ranganathan said. "But if you have enough data examples, you can use deep learning methods to learn the rules of design, even as you are understanding how it works or why it's built that way."

He and his collaborators then created synthetic genes to encode for the proteins, cloned them into bacteria, and watched as the bacteria then made the synthetic proteins using their normal cellular machinery. They found that the artificial proteins had the same catalytic function as the natural chorismate mutase proteins.

A platform to understand other complex systems

Because the design rules are so relatively simple, the number of artificial proteins that researchers could potentially create with them is extremely large.

"The constraints are much smaller than we ever imagined they would be," Ranganathan said. "There is a simplicity in nature's design rules, and we believe similar approaches could help us search for models for design in other complex systems in biology, like ecosystems or the brain."

Though artificial intelligence revealed the design rules, Ranganathan and his collaborators still don't fully understand why the models work. Next they will work to understand just how the models came to this conclusion. "There is much more work to be done," he said.

In the meantime, they also hope to use this platform to develop proteins that can address pressing societal problems, like climate change. Ranganathan and Assoc. Prof. Andrew Ferguson have founded a company called Evozyne that will commercialize this technology with applications in energy, environment, catalysis, and agriculture. Ranganathan has worked with UChicago's Polsky Center for Entrepreneurship and Innovation to file patents and license the IP to the company.

"This system gives us a platform for rationally engineering protein molecules in a way that we always dreamed we could," he said. "Not only can it teach us the physics of how proteins work and how they evolve, it can help us find solutions for issues like carbon capture and energy harvesting. Even more generally, the studies in proteins might even help teach us how the deep neural networks behind modern machine learning actually work."

HANOVER, N.H. - July 24, 2020 - Researchers at Dartmouth, in collaboration with industry partners, have developed software techniques that make lighting in computer-generated images look more realistic. The research will be presented at the upcoming ACM SIGGRAPH conference, the premier venue for research in computer graphics.

The new techniques focus on "real time" graphics which need to maintain the illusion of interactivity as scenes change in response to user moves. These graphics can be used in applications such as video games, extended reality, and scientific visualization tools.

Both papers demonstrate how developers can create sophisticated lighting effects by adapting a popular rendering technique known as ray tracing.

"Over the last decade, ray tracing has dramatically increased the realism and visual richness of computer-generated images in movies where producing just a single frame can take hours," said Wojciech Jarosz, an associate professor of computer science at Dartmouth who served as the senior researcher for both projects. "Our papers describe two very different approaches for bringing realistic ray-traced lighting to the constraints of real time graphics."

The first project, developed with NVIDIA, envisions the possibilities for future games once developers incorporate NVIDIA's hardware-accelerated RTX ray tracing platform. Recent games have started to use RTX for physically correct shadows and reflections, but quality and complexity of lighting is currently limited by the small number of rays that can be traced per frame.

The new technique, called reservoir-based spatiotemporal importance resampling (ReSTIR), creates realistic lighting and shadows from millions of artificial light sources. The ReSTIR approach dramatically increases the quality of rendering on a computer's graphics card by reusing rays that were traced in neighboring pixels and in prior frames.

The new technique can be integrated into the design of future games and works up to 65 times faster than previous rendering techniques.

"This technology is not just exciting for what it can bring to real-time applications like games, but also its impact in the movie industry and beyond," said Benedikt Bitterli, a PhD student at Dartmouth who served as the first author of a research paper on the technique.

The second project, conducted in collaboration with Activision, describes how the video game publisher has incorporated increasingly realistic lighting effects into its games.

Traditionally, video games create lighting sequences in real time using what are called "baked" solutions: the complex ray-traced illumination is computed only once through a time-consuming process. The lighting created using this technique can be displayed easily during gameplay, but it is constrained to assuming a fixed configuration for a scene. As a result, the lighting cannot easily react to the movement of characters and cameras.

The research paper describes how Activision gradually evolved its "UberBake" system from the static approach to one which can depict subtle lighting changes in response to player interactions, such as turning lights on and off, or opening and closing doors.

Since UberBake was developed over many years to work on current games, it needed to work on a variety of existing hardware, ranging from high-end PCs to previous-generation gaming consoles.

"Video games are used by millions of people around the world," said Dario Seyb, a PhD student at Dartmouth who served as the research paper's co-first author. "With so many people interacting with video games, this technology can have a huge impact."

Dartmouth researchers on both projects are affiliated with the Dartmouth Visual Computing Lab.

"These industry collaborations have been fantastic. They allow our students to work on foundational academic research informed by practical problems in industry, allowing the work to have a more immediate, real-world impact," said Jarosz.

The research papers will be published in ACM Transactions on Graphics and presented at SIGGRAPH 2020 taking place online during the summer.

At a glance:

Loss of smell is the main neurological symptom of COVID-19, but the underlying mechanism has been unclear

New study shows infection of nonneuronal supporting cells in the nose and forebrain may be responsible for loss of smell in patients with COVID-19

Findings suggest olfactory sensory neurons are not vulnerable to SARS-CoV-2 infection because they do not express ACE2, a key protein that the virus uses to enter human cells

Results inform efforts to better understand COVID-19-related loss of smell

Temporary loss of smell, or anosmia, is the main neurological symptom and one of the earliest and most commonly reported indicators of COVID-19. Studies suggest it better predicts the disease than other well-known symptoms such as fever and cough, but the underlying mechanisms for loss of smell in patients with COVID-19 have been unclear.

Now, an international team of researchers led by neuroscientists at Harvard Medical School has identified the olfactory cell types most vulnerable to infection by SARS-CoV-2, the virus that causes COVID-19.

Surprisingly, sensory neurons that detect and transmit the sense of smell to the brain are not among the vulnerable cell types.

Reporting in Science Advances on July 24, the research team found that olfactory sensory neurons do not express the gene that encodes the ACE2 receptor protein, which SARS-CoV-2 uses to enter human cells. Instead, ACE2 is expressed in cells that provide metabolic and structural support to olfactory sensory neurons, as well as certain populations of stem cells and blood vessel cells.

The findings suggest that infection of nonneuronal cell types may be responsible for anosmia in COVID-19 patients and help inform efforts to better understand the progression of the disease.

"Our findings indicate that the novel coronavirus changes the sense of smell in patients not by directly infecting neurons but by affecting the function of supporting cells," said senior study author Sandeep Robert Datta, associate professor of neurobiology in the Blavatnik Institute at HMS.

This implies that in most cases, SARS-CoV-2 infection is unlikely to permanently damage olfactory neural circuits and lead to persistent anosmia, Datta added, a condition that is associated with a variety of mental and social health issues, particularly depression and anxiety.

"I think it's good news, because once the infection clears, olfactory neurons don't appear to need to be replaced or rebuilt from scratch," he said. "But we need more data and a better understanding of the underlying mechanisms to confirm this conclusion."

A majority of COVID-19 patients experience some level of anosmia, most often temporary, according to emerging data. Analyses of electronic health records indicate that COVID-19 patients are 27 times more likely to have smell loss but are only around 2.2 to 2.6 times more likely to have fever, cough or respiratory difficulty, compared to patients without COVID-19.

Some studies have hinted that anosmia in COVID-19 differs from anosmia caused by other viral infections, including by other coronaviruses.

For example, COVID-19 patients typically recover their sense of smell over the course of weeks--much faster than the months it can take to recover from anosmia caused by a subset of viral infections known to directly damage olfactory sensory neurons. In addition, many viruses cause temporary loss of smell by triggering upper respiratory issues such as stuffy nose. Some COVID-19 patients, however, experience anosmia without any nasal obstruction.

Pinpointing vulnerability

In the current study, Datta and colleagues set out to better understand how sense of smell is altered in COVID-19 patients by pinpointing cell types most vulnerable to SARS-CoV-2 infection.

They began by analyzing existing single-cell sequencing datasets that in total catalogued the genes expressed by hundreds of thousands of individual cells in the upper nasal cavities of humans, mice and nonhuman primates.

The team focused on the gene ACE2, widely found in cells of the human respiratory tract, which encodes the main receptor protein that SARS-CoV-2 targets to gain entry into human cells. They also looked at another gene, TMPRSS2, which encodes an enzyme thought to be important for SARS-CoV-2 entry into the cell.

The analyses revealed that both ACE2 and TMPRSS2 are expressed by cells in the olfactory epithelium--a specialized tissue in the roof of the nasal cavity responsible for odor detection that houses olfactory sensory neurons and a variety of supporting cells.

Neither gene, however, was expressed by olfactory sensory neurons. By contrast, these neurons did express genes associated with the ability of other coronaviruses to enter cells.

The researchers found that two specific cell types in the olfactory epithelium expressed ACE2 at similar levels to what has been observed in cells of the lower respiratory tract, the most common targets of SARS-CoV-2, suggesting a vulnerability to infection.

These included sustentacular cells, which wrap around sensory neurons and are thought to provide structural and metabolic support, and basal cells, which act as stem cells that regenerate the olfactory epithelium after damage. The presence of proteins encoded by both genes in these cells was confirmed by immunostaining.

In additional experiments, the researchers found that olfactory epithelium stem cells expressed ACE2 protein at higher levels after artificially induced damage, compared with resting stem cells. This may suggest additional SARS-CoV-2 vulnerability, but it remains unclear whether or how this is important to the clinical course of anosmia in patients with COVID-19, the authors said.

Datta and colleagues also analyzed gene expression in nearly 50,000 individual cells in the mouse olfactory bulb, the structure in the forebrain that receives signals from olfactory sensory neurons and is responsible for initial odor processing.

Neurons in the olfactory bulb did not express ACE2. The gene and associated protein were present only in blood vessel cells, particularly pericytes, which are involved in blood pressure regulation, blood-brain barrier maintenance and inflammatory responses. No cell types in the olfactory bulb expressed the TMPRSS2 gene.

Smell loss clue

Together, these data suggest that COVID-19-related anosmia may arise from a temporary loss of function of supporting cells in the olfactory epithelium, which indirectly causes changes to olfactory sensory neurons, the authors said.

"We don't fully understand what those changes are yet, however," Datta said. "Sustentacular cells have largely been ignored, and it looks like we need to pay attention to them, similar to how we have a growing appreciation of the critical role that glial cells play in the brain."

The findings also offer intriguing clues into COVID-19-associated neurological issues. The observations are consistent with hypotheses that SARS-CoV-2 does not directly infect neurons but may instead interfere with brain function by affecting vascular cells in the nervous system, the authors said. This requires further investigation to verify, they added.

The study results now help accelerate efforts to better understand smell loss in patients with COVID-19, which could in turn lead to treatments for anosmia and the development of improved smell-based diagnostics for the disease.

"Anosmia seems like a curious phenomenon, but it can be devastating for the small fraction of people in whom it's persistent," Datta said. "It can have serious psychological consequences and could be a major public health problem if we have a growing population with permanent loss of smell."

The team also hope the data can help pave inroads for questions on disease progression such as whether the nose acts as a reservoir for SARS-CoV-2. Such efforts will require studies in facilities that allow experiments with live coronavirus and analyses of human autopsy data, the authors said, which are still difficult to come by. However, the collaborative spirit of pandemic-era scientific research calls for optimism.

"We initiated this work because my lab had a couple of datasets ready to analyze when the pandemic hit, and we published an initial preprint," Datta said. "What happened after that was amazing, researchers across the globe offered to share and merge their data with us in a kind of impromptu global consortium. This was a real collaborative achievement."

A new study of human olfactory cells has revealed that viral invasion of supportive cells in the nasal cavity might be driving the loss of smell seen in some patients with COVID-19. The findings show that non-neuronal cells in the brain and nose express genes critical for SARS-CoV-2 entry, while neurons do not; therefore, non-neuronal cells are likely to be the primary targets for virus-induced damage leading to loss of smell, or anosmia. Recent investigations into COVID-19-associated anosmia showed that cells from the human upper airway express high levels of receptor genes involved in SARS-CoV-2 entry, suggesting that these respiratory epithelial cells serve as viral reservoirs during CoV-2 infection. However, these studies did not investigate the sheet of cells that line the nasal cavity, called the olfactory epithelium - the first entryway for pathogens before they reach the respiratory epithelium. Using bulk RNA sequencing of human cells from the nasal mucosa, David Brann and colleagues identified cell types in the olfactory epithelium in the nose and the brain's olfactory bulb that express two key receptor genes involved in SARS-CoV-2 entry, ACE2 and TMPRSS2. Single cell RNA sequencing of these cells and neurons provided the key insight that neither gene was detected in olfactory neurons, but both were highly expressed by support cells, stem cells, and perivascular cells in the nose and brain. Fluorescent staining of ACE2 in olfactory cells in mice confirmed this result and revealed pervasive expression of ACE2 protein in structural support cells of the nose and in cells that wrap around the capillaries of the olfactory bulb. Identifying the mechanisms that underlie the olfactory symptoms of COVID-19 can help lead to new diagnostics for SARS-CoV-2 infection, yield insights into the cellular dynamics of the nose, and propel future treatments for anosmia, the authors say.

A new study found raised levels of transforming growth factor beta-induced protein (TGFBIp) in blood sampled from roughly 100 people hospitalized for COVID-19, and further found that elevated levels of both the normal and acetylated forms of TGFBIp correlated with the severity of disease symptoms in these patients. While more work will be required to determine whether heightened levels of acetylated TGFBIp can serve as an exclusive, specific, and reliable diagnostic indicator for the severity of COVID-19, the research also suggests that TGFBIp could be a viable therapeutic target to treat severe inflammation - including deadly "cytokine storms" - in patients suffering from severe cases of the disease. While much work has been done to characterize the immune responses of patients with COVID-19, the inflammatory markers and cytokines known to be induced by SARS-CoV-2 infection are often short-lived. Hee Ho Park and colleagues set out to investigate whether increased levels of both the normal and acetylated forms of TGFBIp, a more stable molecule known to activate the immune-regulating transcription factor NF-κB, might serve as a more lasting signal of SARS-CoV-2 infection. The researchers analyzed blood samples from healthy controls and two cohorts of COVID-19 patients: those admitted to a hospital for treatment with relatively mild symptoms, and those who required ICU care to treat acute respiratory distress syndrome (ARDS) and/or sepsis. Compared with the healthy controls, both patient cohorts exhibited elevated levels of TGFBIp, as well as higher levels of acetylated TGFBIp, with the ICU patients exhibiting even greater levels of both protein forms. Upon treating immune cells taken from these patients with antibodies that neutralize TGFBIp, the researchers also observed a decrease in the production of inflammatory cytokines. While further work will be required to validate these results and assess the safety of the neutralizing antibodies, the finding nonetheless suggests that TGFBIp could be targeted to help treat severe inflammation in COVID-19 patients.

Current observations suggest that the coronavirus SARS-CoV-2 causes severe symptoms mainly in elderly patients with chronic disease. However when two pairs of previously healthy young brothers from two families required mechanical ventilation at the intensive care unit in rapid succession, doctors and researchers at Radboud University Medical Center were inclined to consider that genetic factors had a key role in compromising their immune system. Their research identified the gene TLR7 as an essential player in the immune response against SARS-CoV-2. A finding with potentially major consequences for understanding and possibly treatment of COVID-19.

During the wave of COVID-19 patients that flooded Dutch hospitals in the first half of 2020, two young brothers became seriously ill with the SARS-CoV-2 virus and had to be mechanically ventilated in the ICU. One of them died from the consequences of the infection, the other recovered. The severe course of disease in otherwise healthy young brothers was a relatively rare occurrence, especially because the virus mainly affects the elderly. This observation triggered the curiosity of an attentive physician from the MUMC+ department of clinical genetics. She contacted her colleagues in Nijmegen who then investigated why these two young brothers were so severely affected.

Genetic factors

"In such a case, you immediately wonder whether genetic factors could play a role," says geneticist Alexander Hoischen. "Getting sick from an infection is always an interplay between - in this case - the virus and the human immune system. It may be a mere coincidence that two brothers from the same family become so severely ill. But it is also possible that an inborn error of the immune system has played an important role. We investigated this possibility, together with our multidisciplinary team at Radboudumc."

One X-chromosome

All genes (collectively called the exome) of both brothers were sequenced, after which the investigators combed through the data searching for a possible shared cause. Cas van der Made, PhD student and resident at the department of Internal Medicine: "We mainly looked at genes that play a role in the immune system. We know that several of these genes are located on the X-chromosome, and with two brother pairs affected X-chromosomal genes were most suspicious. Women carry two X-chromosomes, while men possess a Y-chromosome apart from the X. Therefore, men have only one copy of the X-chromosomal genes. In case men have a defect in such a gene, there is no second gene that can take over that role, as in women."

Gene identification

That search quickly revealed mutations in the gene encoding for the Toll-like receptor 7, TLR7 for short. There are multiple TLR-genes, which belong to a family of receptors with an important role in the recognition of pathogens (such as bacteria and viruses) and the activation of the immune system. Hoischen: "A few letters were missing in the genetic code of the TLR7 gene. As a result, the code cannot be read properly and hardly any TLR7 protein is produced. TLR7 function has so far never been associated with an inborn error of immunity. But unexpectedly we now have an indication that TLR7 is essential for protection from this coronavirus. So it seems that the virus can replicate undisturbed because the immune system does not get a message that the virus has invaded. Because TLR7, which must identify the intruder and subsequently activate the defense, is hardly present. That could be the reason for the severity of the disease in these brothers."

Additional confirmation

Then, quite unexpectedly, the doctors and researchers at Radboudumc come across another pair of brothers who have fallen seriously ill with COVID-19. Again, they are both under 35 years of age. Both of them were also in the ICU for mechanical ventilation. "Then the question of the role of genetics became even more obvious." says Hoischen. "We also investigated the genetic code of these two brothers, again via the 'rapid-clinical exome' method. This time we saw no deletion, no loss of letters, but a single spelling mistake of one DNA-letter of the TRL7 gene. The effect on the gene is the same, however, because these brothers also do not make sufficient functional TLR7 protein. Suddenly we had four young people with a defect in the same gene, all of whom had fallen seriously ill from the SARS-CoV-2 virus."

Essential role in the defense

Van der Made and colleagues have investigated the consequences of improper functioning of the TLR7 receptor. "Once activated, TLR7 triggers the production of so-called interferons, signaling proteins that are essential in the defense against virus infections," says van der Made. "This immune response is perhaps all the more important in the fight against the SARS-CoV-2 virus, because we know from the literature that the virus has tricks to reduce the production of interferons by immune cells. When we mimic an infection with the coronavirus, we see that immune cells of the patients without properly functioning TLR7 hardly respond, and that minimal amounts of interferons are produced. These tests make it clear that the virus appears to have free rein in people without properly functioning TLR7 because it [the virus] is not recognized by the immune system."

Consequences

"Due to the serious illness of four brothers in two families, so serious that it cost one of the young men his life, we have discovered this condition," says Hoischen. "It seems to be a very specific abnormality, an immunodeficiency, which is mainly related to this coronavirus. None of the four men have previously suffered from immune-related diseases. It is the first time that we can connect a clinical phenomenon so strongly with TLR7."

"This discovery not only provides us with more insight into the fundamental workings of the immune system, but it may also have important consequences for the treatment of severely ill COVID-19 patients," says Frank van de Veerdonk, immunologist and infectiologist. "The substance interferon can be given as a therapy. It is currently being investigated whether administering interferon in COVID-19 can indeed help."

Living under a translucent rock can be quite comfortable -- if you're a moss in the Mojave Desert.

A graduate student at the University of California, Berkeley, found that some mosses in the California desert seek protection from the relentless sun and heat by sheltering under translucent quartz pebbles, essentially using the rocks as sunshades.

The soil under these rocks retains more moisture than exposed desert soil, said Jenna Ekwealor, while enough light leaks through the milky quartz to allow the tiny mosses to remain green with chlorophyll. Mosses actually prefer dim light, making these conditions ideal for growth. In contrast, nearby mosses in full sun are dried up and black.

One species of desert moss seems able to survive at high elevations only under the milky quartz, which occurs in outcroppings scattered around the desert. Mosses don't grow under granitic stones in the area because sunlight can't get through to the soil.

"We were there (in the Mojave) studying the population biology and reproductive biology of mosses, and picking up these cool quartz rocks, like, oh look at this pretty rock," said Ekwealor, an integrative biology doctoral student who works in the University and Jepson Herbaria at UC Berkeley. While all the other mosses were dry and dormant, she "saw that there was moss growing underneath the quartz and it was bright green. That was the first clue that something was different, that they were responding to the environment differently."

Working with her former master's thesis advisor, Kirsten Fisher of California State University, Los Angeles, they placed temperature and humidity sensors under milky quartz pebbles to record the microclimate from September of last year to February of 2020.

"The rock acts as a buffer for the extremes of the climate," Ekwealor said. "The desert is at a high elevation, it gets really hot in the summer and really cold in the winter. And days can be hot, and nights can be cold. The rock keeps the mosses underneath cooler during the hot parts of the year and warmer during the cold periods. The increased relative humidity was just a positive, an important thing for these plants that dry out when the relative humidity is too low."

Astrobiologists have long studied cyanobacteria that live under translucent desert rocks -- a possible model for the types of extreme life that could exist on other planets -- but this is the first green plant known to take advantage of these natural refuges.

"In the desert, for all organisms, it is like life or death all the time," she said. "So anytime you can find a little boost, a little benefit, it makes a really big difference."

Ekwealor and Fisher reported their discovery this week in the journal PLOS ONE.

Cool mosses

As one of the first land plants to evolve more than 300 million years ago, mosses are well adapted to extreme environments, able to survive repeated desiccation and freezing. Some produce sunscreens to protect against intense ultraviolet sunlight. Some can remain essentially dead, with zero metabolic activity, for a decade, and then revive in seconds when wetted. They're found in the Arctic and Antarctic as well as the hottest, driest deserts.

One of the moss species that often lives under milky quartz, Syntrichia caninervis, typically grows on exposed soil in biocrusts, an association with lichens and cyanobacteria. These crusts are a feature of many deserts, protecting the soil from erosion and providing nutrients for other plants.

As part of the desert's biological crust, Syntrichia are inconspicuous -- about 1 millimeter in diameter and 5 millimeters long. They grow only when wet, and since the Mojave may get only five "precipitation events" per year -- half of which could be snow, which is not conducive to growth -- they grow slowly. Ekwealor estimates that Syntrichia grows only a couple of millimeters per year.

The rest of the time, the Syntrichia mosses on exposed soil remain dormant, turning a dark brown-black, possibly as a sunscreen -- something Ekwealor is trying to figure out for her Ph.D. thesis.

She found that, in contrast to the exposed mosses, mosses that crawl under a rock grow about 60% faster.

"The mosses that normally live at that elevation are small and brown on the soil surface, and under the rocks they are tall and green," she said.

At its lowest, the average relative humidity under the rocks was about twice that of exposed soil -- 63% versus 33%. The daily temperature swing in the "hypolithic microenvironment" was reduced by about 4 degrees Celsius (7 degrees Fahrenheit) from that on the soil surface.

A second moss species, Tortula inermis, grows commonly in full sun at lower altitudes, but at the elevation of the study site, 1,900 meters (6,200 feet), it appears to grow only under milky quartz.

"The rocks offer mosses two big benefits: either a boost in their normal habitat, or they get to live in a habitat that you wouldn't normally live in," Ekwealor said.

Though mosses prefer dim, moist conditions, they, like all plants, require some light or they turn white and die. According to her measurements, between 4% and 0.4% of incident light is transmitted through milky quartz rocks, depending on the size of the rock. At her study site, in a place called Sheep Creek Wash, the quartz ranged in thickness from 25 to 14 millimeters, or an inch to two-fifths of an inch.

The researchers suspect that the quartz not only reduces the overall light and heat, but also provides protection from damaging UV rays. Mosses growing under quartz had less pigmented sunscreen than those growing in exposed areas.

A self-described "moss evangelist," Ekwealor is fascinated by the tiny world of mosses, and occasionally leads local moss walks for the bryophyte chapter of the California Native Plant Society.

"For these tiny plants, a thing like this giant quartz rock over you blocking out all the sun and keeping you wet -- it is like a huge habitat," she said. "You can be in the middle of the desert, but a small rock makes you feel like you are in a spring. We have to remember to see the world from the perspective of a very small plant."

Tiny, 3D-printed bricks have been designed to heal broken bones -- and could one day lead to lab-made organs for human transplant.

Inspired by Lego blocks, the small, hollow bricks serve as scaffolding onto which both hard and soft tissue can regrow better than today's standard regeneration methods, according to new research published in Advanced Materials. Each brick is 1.5 millimeters cubed, or roughly the size of a small flea.

"Our patent-pending scaffolding is easy to use; it can be stacked together like Legos and placed in thousands of different configurations to match the complexity and size of almost any situation," said Luiz Bertassoni, Ph.D., who led the technology's development and is an associate professor in the OHSU School of Dentistry and an associate professor of biomedical engineering in the OHSU School of Medicine.

Bertassoni partnered with colleagues from OHSU, University of Oregon, New York University and Mahidol University in Thailand to develop and evaluate the technology.

When stacked together, the microcages are designed to repair broken bones better than today's methods. Orthopaedic surgeons typically repair more complex bone fractures by implanting metal rods or plates to stabilize the bone and then inserting bio-compatible scaffolding materials packed with powders or pastes that promote healing.

A unique advantage of this new scaffolding system is that its hollow blocks can be filled with small amounts of gel containing various growth factors that are precisely placed closest to where they are needed. The study found growth factor-filled blocks placed near repaired rat bones led to about three times more blood vessel growth than conventional scaffolding material.

"The 3D-printed microcage technology improves healing by stimulating the right type of cells to grow in the right place, and at the right time," said study co-author Ramesh Subbiah, Ph.D., a postdoctoral scholar in Bertassoni's OHSU lab who specializes in growth factor delivery. "Different growth factors can be placed inside each block, enabling us to more precisely and quickly repair tissue."

The small devices are modular and can be assembled to fit into almost any space. When piecing together block segments containing four layers of four-bricks-by-four bricks, the researchers estimate more than 29,000 different configurations can be created.

Bertassoni and colleagues also imagine their 3D-printed technology could be used to heal bones that have to be cut out for cancer treatment, for spinal fusion procedures and to build up weakened jaw bones ahead of a dental implant.

And, by changing the composition of the technology's 3D-printed materials, they envision it could also be used to build or repair soft tissues. With significantly more research, they hope the modular microcage approach could even be used to make organs for transplant.

Bertassoni and his team will further explore the microcages' performance in bone repair. They plan to test the technology's ability to repair more complex bone fractures in rats or larger animals.

If physical distancing measures in the United States are relaxed while there is still no COVID-19 vaccine or treatment and while personal protective equipment remains in short supply, the number of resulting infections could be about the same as if distancing had never been implemented to begin with, according to a UCLA-led team of mathematicians and scientists.

The researchers compared the results of three related mathematical models of disease transmission that they used to analyze data emerging from local and national governments, including one that measures the dynamic reproduction number -- the average number of susceptible people infected by one previously infected person. The models all highlight the dangers of relaxing public health measures too soon.

"Distancing efforts that appear to have succeeded in the short term may have little impact on the total number of infections expected over the course of the pandemic," said lead author Andrea Bertozzi, a distinguished professor of mathematics who holds UCLA's Betsy Wood Knapp Chair for Innovation and Creativity. "Our mathematical models demonstrate that relaxing these measures in the absence of pharmaceutical interventions may allow the pandemic to reemerge. It's about reducing contact with other people, and this can be done with PPE as well as distancing."

The study is published in the journal Proceedings of the National Academy of Sciences and is applicable to both future spikes of COVID-19 and future pandemics, the researchers say.

If distancing and shelter-in-place measures had not been taken in March and April, it is very likely the number of people infected in California, New York and elsewhere would have been dramatically higher, posing a severe burden on hospitals, Bertozzi said. But the total number of infections predicted if these precautions end too soon is similar to the number that would be expected over the course of the pandemic without such measures, she said. In other words, short-term distancing can slow the spread of the disease but may not result in fewer people becoming infected.

Mathematically modeling and forecasting the spread of COVID-19 are critical for effective public health policy, but wide differences in precautionary approaches across the country have made it a challenge, said Bertozzi, who is also a distinguished professor of mechanical and aerospace engineering. Social distancing and wearing face masks reduce the spread of COVID-19, but people in many states are not following distancing guidelines and are not wearing masks -- and the number of infections continues to rise.

What are the implications of these findings for policymakers who want to relax social distancing in an effort to revive their economies?

"Policymakers need to be careful," Bertozzi said. "Our study predicts a surge in cases in California after distancing measures are relaxed. Alternative strategies exist that would allow the economy to ramp up without substantial new infections. Those strategies all involve significant use of PPE and increased testing."

During the 1918 influenza pandemic, social distancing was first enforced and then relaxed in some areas. Bertozzi points to a study published in Proceedings of the National Academy of Sciences in 2007 that looked at several American cities during that pandemic where a second wave of infections occurred after public health measures were removed too early.

That study found that the timing of public health interventions had a profound influence on the pattern of the second wave of the 1918 pandemic in different cities. Cities that had introduced measures early in the pandemic achieved significant reductions in overall mortality. Larger reductions in peak mortality were achieved by those cities that extended the public health measures for longer. San Francisco, St. Louis, Milwaukee and Kansas City, for instance, had the most effective interventions, reducing transmission rates by 30% to 50%.

"Researchers Martin Bootsma and Neil Ferguson were able to analyze the effectiveness of distancing measures by comparing the data against an estimate for what might have happened had distancing measures not been introduced," Bertozzi said of the 2007 study. "They considered data from the full pandemic, while we addressed the question of fitting models to early-time data for this pandemic. During the 1918 influenza pandemic, the early relaxation of social distancing measures led to a swift uptick in deaths in some U.S. cities. Our mathematical models help to explain why this effect might occur today."

The COVID-19 data in the new study are from April 1, 2020, and are publicly available. The study is aimed at scientists who are not experts in epidemiology.

"Epidemiologists are in high demand during a pandemic, and public health officials from local jurisdictions may have a need for help interpreting data," Bertozzi said. "Scientists with relevant background can be tapped to assist these people."

You're faced with a big decision so your second brain provides what's normally referred to as 'gut instinct', but how did this sensation reach you before it was too late?

The Enteric Nervous System (ENS) is an extensive network of neurons and transmitters wrapped in and around the human gut with the prime function of managing digestion, but researchers at Flinders University are delving into the complexity of this brain like system to uncover it's secret capabilities.

In a new study published in the eNeuro journal, Professor Nick Spencer's laboratory has identified a particular type of neuron in the gut wall that communicates signals to other neurons outside the gut, near the spinal cord and up to the brain.

"There is significant interest in how the gut communicates with the brain as a major unresolved issue because of growing evidence that many diseases may first start in the gut and then travel to the brain, an example of which is Parkinson's Disease," says Professor Spencer.

"The new study has uncovered how viscerofugal neurons provide a pathway so our gut can "sense" what is going on inside the gut wall, then relay this sensory information more dynamically than was previously assumed to other organs, like the spinal cord and brain which influence our decisions, mood and general wellbeing."

The results reveal why the ENS might play an increasingly important part on human health, and could shed light on potential new treatments for conditions like Parkinson's disease.

This study represents a big step towards understanding ENS functions and the complexity of the gut and brain connection through the neurons that allow communication in the body.

Professor Spencer says there is increasing interest in understanding how the nervous system in the gut (ENS) communicates with the brain, to give us all those sensations we know of.

"What is particularly exciting about the gut, is that it is unlike all other internal organs (e.g. heart, liver, bladder) because the gut has its own nervous system, which can function independently of the brain or spinal cord. Understanding how the gut communicates and controls other organs in the body can lead to important breakthroughs for disease treatment and this is an important step in the right direction."

What The Article Says: In this essay, an experienced oncologist mourns the loss of personal connection with patients and their families that has resulted from the social distancing of the COVID-19 era.

Authors: Hanna K. Sanoff, M.D., of the University of North Carolina, Chapel Hill, 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/jamaoncol.2020.2839)

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

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Researchers are urging city-dwellers to switch off their garden lights at night-time after a study of magpies and pigeons revealed the harmful impact artificial light is having on the birds' sleep patterns.

The study by La Trobe University and University of Melbourne, published today in Current Biology, is the first to measure neurological responses to light pollution in wildlife.

The researchers looked at how birds' sleep was affected by artificial white light and the apparently more "sleep-friendly" amber light.

They found light comparable in intensity to street lighting can disrupt the length, structure and intensity of sleep in magpies and pigeons, regardless of the light's colour.

Utilising miniature sensors to measure magpie and pigeon brain activity, researchers found their non-rapid eye movement (NREM) and REM sleep cycles were altered when exposed to white and amber lighting at night, but that the magnitude of these effects differed between the species.

La Trobe University sleep expert Dr John Lesku said that while magpie sleep is more disrupted under white light compared to amber light, both types of light are equally disruptive for sleep in pigeons.

"Both magpies and pigeons average 10 hours of sleep per night. We found that magpies lost more NREM sleep under white light than amber light. By comparison, pigeons lost around 4 hours of sleep under both white and amber light," Dr Lesku said.

"Interestingly, neither species fully recovered sleep lost to white or amber light exposure."

University of Melbourne and La Trobe University researcher Dr Anne Aulsebrook said changes to sleeping patterns in birds, caused by human light pollution, is concerning.

"We know sleep is important for animals to not only function, but thrive," Dr Aulsebrook said.

"While amber lighting appears to have a less damaging impact than white light on magpies, our findings suggest the relative impacts of light pollution on birds may be species-specific. Amber lighting can reduce sleep disruption in some birds, but it is not a solution for all species.

"Additionally, disrupted sleeping patterns that force birds to catch up on sleep in the daytime could impact their ability to forage for food, fight off predators and search for mates."

University of Melbourne and La Trobe University graduate researcher Farley Connelly recommended further research into avian circadian rhythms and the implementation of short-term solutions.

"We should think about using artificial light only as and where it's needed," Mr Connelly said.

"Switch off that porch light, install sensor lights, remove decorative lights from trees, balconies and other outdoor settings, and keep street and park lights directed to the ground or shielded where possible.

"And if you're ever woken by the early call of a magpie, remember it could be just as sleep deprived as you are."

Throughout history, spikes in mortality due to wars and famines were followed by increased births, while the Spanish Flu resulted in a temporary drop in fertility before recovering during a "baby boom." Contrary to this historic trend, the Covid-19 health emergency will plausibly cause a decline in fertility, without the factors that have brought on a baby boom in the past, according to "The Covid-19 pandemic and human fertility" published on July 24 by Science Magazine, the peer-reviewed journal of the American Association for the Advancement of Science, by Bocconi University's Arnstein Aassve, Nicolò Cavalli, Letizia Mencarini and Samuel Plach, and Massimo Livi Bacci from University of Florence.

The authors emphasize differences in populations' development and their stage in the demographic transition to accurately draw conclusions from the existing research.

"Although it is difficult to make precise predictions, a likely scenario is that fertility will fall, at least in high-income countries and in the short run," said Arnstein Aassve, Professor at the Department of Social and Political Sciences at Bocconi and at the Carlo F. Dondena Centre for Research on Social Dynamics and Public Policy.

This study is part of the Dondena Centre's research activities within Bocconi's Covid Crisis Lab.

In high-income countries, disruption in the organization of family life due to prolonged lockdowns, the reinternalization of childcare within the couple following school closures, and deteriorating economic outlooks are likely to lead to postponements in childbearing. A further fertility fall in high-income countries will accelerate population ageing and population decline, with implications for public policy.

In low- and middle-income countries the fertility decline observed in recent decades from trends such as urbanization, economic development and female occupation is unlikely to be fundamentally reversed by economic setbacks. Difficulties, though, in accessing family planning services might result in a short-run spike in unintended pregnancies and worsening neonatal and reproductive health.

Home-made cloth face masks likely need a minimum of two layers, and preferably three, to prevent the dispersal of viral droplets from the nose and mouth that are associated with the spread of COVID-19, indicates a video case study published online in the journal Thorax.

Viral droplets are generated during coughing, sneezing, or speaking. And face masks are thought to protect healthy people from inhaling infectious droplets as well as reducing the spread from those who are already infected.

But worldwide shortages of personal protective equipment during the pandemic have led some health agencies, such as the US Centers for Disease Control (CDC), to recommend the use of home-made cloth face coverings as an alternative to surgical face masks.

Several types of material have been suggested for these, but based on little or no evidence of how well they work.

A team of Australian researchers therefore compared the effectiveness of single and double-layer cloth face coverings (175 g/m² cotton fabric, with a thread count of 170/ inch) with a 3-ply surgical face mask (Bao Thach) at reducing droplet spread.

The single layer covering was made from a folded piece of cotton T shirt and hair ties; the double layer covering was made using the sew method, as set out by CDC:
https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/how-to-make-cloth-face-covering.html

The researchers used a tailored LED lighting system and a high-speed camera to film the dispersal of airborne droplets produced by a healthy person with no respiratory infection, during speaking, coughing, and sneezing while wearing each type of mask.

The video recording showed that the 3-ply surgical face mask was the most effective at reducing airborne droplet dispersal, although even a single layer cloth face covering reduced the droplet spread from speaking.

But a double layer covering was better than a single layer in reducing the droplet spread from coughing and sneezing, the recording showed.

This is just one case, added to which several other factors contribute to the effectiveness of cloth face masks, note the researchers. These include the type of material used, design and fit, as well as the frequency of washing.

Nevertheless, based on their observations, a home made cloth mask with at least two layers is preferable to a single layer mask, they say, adding: "Guidelines on home-made cloth masks should stipulate multiple layers."

And they emphasise: "There is a need for more evidence to inform safer cloth mask design, and countries should ensure adequate manufacturing or procurement of surgical masks."

This quiet period, likely caused by the total global effect of social distancing measures, closure of services and industry, and drops in tourism and travel, is the longest and most pronounced quiet period of seismic noise in recorded history.

The new research, led by the Royal Observatory of Belgium and five other institutions around the world including Imperial College London, showed that the dampening of 'seismic noise' caused by humans was more pronounced in more densely populated areas.

The relative quietness allowed researchers to listen in to previously concealed earthquake signals, and could help us differentiate between human and natural seismic noise more clearly than ever before.

Co-author Dr Stephen Hicks, from Imperial's Department of Earth Science and Engineering, said: "This quiet period is likely the longest and largest dampening of human-caused seismic noise since we started monitoring the Earth in detail using vast monitoring networks of seismometers.

"Our study uniquely highlights just how much human activities impact the solid Earth, and could let us see more clearly than ever what differentiates human and natural noise."

The paper is published today in Science.

Anthropause

Measured by instruments called seismometers, seismic noise is caused by vibrations within the Earth, which travel like waves. The waves can be triggered by earthquakes, volcanoes, and bombs - but also by daily human activity like travel and industry.

Although 2020 has not seen a reduction in earthquakes, the drop in human-caused seismic noise is unprecedented. The strongest drops were found in urban areas, but the study also found signatures of the lockdown on sensors buried hundreds of metres underground and in more remote areas.

Human-generated noise usually dampens during quiet periods like over the Christmas/New Year period and Chinese New Year, and during weekends and overnight. However, the drop in vibrations caused by COVID-19 lockdown measures eclipse even those seen during these periods.

Some researchers are dubbing this drop in anthropogenic (human-caused) noise and pollution the 'anthropause'.

Dr Hicks said: "This is the first global study of the impact of the coronavirus anthropause on the solid Earth beneath our feet."

To gather the data, researchers looked at seismic data from a global network of 268 seismic stations in 117 countries and found significant noise reductions compared to before any lockdown at 185 of those stations. Beginning in China in late January 2020, and followed by Europe and the rest of the world in March to April 2020, researchers tracked the 'wave' of quietening between March and May as worldwide lockdown measures took hold.

The largest drops in vibrations were seen in the most densely populated areas, like Singapore and New York City, but drops were also seen in remote areas like Germany's Black Forest and Rundu in Namibia.
Citizen-owned seismometers, which tend to measure more localised noise, noted large drops around universities and schools around Cornwall, UK and Boston, USA - a drop in noise 20 per cent larger than seen during school holidays.
Countries like Barbados, where lockdown coincided with the tourist season, saw a 50 per cent decrease in noise. This coincided with flight data that suggested tourists returned home in the weeks before official lockdown.

Listening in

Over the past few decades, seismic noise has gradually increased as economies and populations have grown.

The drastic changes to daily life caused by the pandemic have provided a unique opportunity to study their environmental impacts, such as reductions in emissions and pollution in the atmosphere. The changes have also given us the opportunity to listen in to the Earth's natural vibrations without the distortions of human input.

The study reports the first evidence that previously concealed earthquake signals, especially during daytime, appeared much clearer on seismometers in urban areas during lockdown.

The researchers say the lockdown quietening could also help them differentiate between human-caused noise and natural signals that might warn of upcoming natural disasters.

Lead author Dr Thomas Lecocq from the Royal Observatory of Belgium said: "With increasing urbanisation and growing global populations, more people will be living in geologically hazardous areas. It will therefore become more important than ever to differentiate between natural and human-caused noise so that we can 'listen in' and better monitor the ground movements beneath our feet. This study could help to kick-start this new field of study."

The study's authors hope that their work will spawn further research on the seismic lockdown, as well as finding previously hidden signals from earthquakes and volcanoes.

Dr Hicks said: "The lockdowns caused by the coronavirus pandemic may have given us a glimmer of insight into how human and natural noise interact within the Earth. We hope this insight will spawn new studies that help us listen better to the Earth and understand natural signals we would otherwise have missed."