Culture

The death cap mushroom is highly toxic. However, some of its toxins can also be healing: amanitins are potential components for antibody-based cancer treatments. In the journal Angewandte Chemie, German scientists have now introduced a new synthetic route for α-amanitin. Their method seems suitable for production on a larger scale, finally making enough of the toxin available for further research.

Amanitins inhibit the enzyme RNA polymerase II with high selectivity, which leads to cell death. When transported into tumor cells by antibodies, the toxin could fight tumors. Until recently, however, the only source of amanitins was the mushrooms (Amanita phalloides) themselves, which limited the possibilities for experimentation.

Some time ago, a total synthesis was reported for α-amanitin, the most powerful amanitin. Researchers working with Roderich D. Süssmuth at the Technical University of Berlin have now introduced an alternative route for a total synthesis that occurs entirely in the liquid phase, allows for the possibility of producing different structural variants, and can be implemented on a larger scale. "We decided to use a convergent route, meaning that several components are first synthesized independently and then finally put together to form the target molecule," explains Süssmuth. The building blocks are three peptide fragments made of five, one, and two amino acids. The researchers refer to their method as a [5+1+2] synthesis.

Amatoxins are ring-shaped peptides made of eight amino acids that have an additional internal cross-ring bond between the amino acids tryptophan and cysteine, known as a tryptathionine. Instead of forming the required thioether bond at the end of their synthesis, the researchers made a building block from five amino acids that already contain the tryptathionine.

The key step for the formation of the other two peptide fragments was the development of routes for the production of the amino acids 6-hydroxytryptophan (Htp) and (3R,4R)-L-4,5-dihydroxyisoleucin (Dhil) in multigram quantities--a big challenge. Neither of these compounds is proteinogenic, meaning they are not coded in DNA. For this synthesis, they must be enantiomerically pure, with a very specific spatial arrangement of all of the atoms within the molecule. The researchers developed a seven-step synthesis for the production of Dhil--the shortest synthetic route to this type of amino acid reported to date. "We consider our new synthetic routes for Dhil and Htp to be industrially usable," says Süssmuth. "Our α-amanitin synthesis is the first to be carried out entirely in the liquid phase. This offers access to larger amounts of alpha-amanitin for study as a potential cancer treatment. In addition, it could be the starting point for future industrial production of drugs based on amanitin."

Weighing in on a debate that has raged for decades, Penn State researchers, after conducting a series of ultra-detailed comparisons, have declared that shipping pallets made of wood are slightly more environmentally friendly and sustainable than those made of plastic.

"Few people realize the significance of this issue -- there are about 700 million pallets produced and recycled each year in the United States alone," said Chuck Ray, associate professor of ecosystem science and management in the College of Agricultural Sciences. "There are 4 billion pallets in use in this country."

Researchers compared the long-term performance of treated wooden and plastic pallets through a detailed, cradle-to-grave life-cycle assessment, and conducted an analysis of treatments required to kill pests such as insects. They investigated and evaluated the environmental impacts of resources consumed and emissions released by wooden and plastic pallets throughout their life cycles.

In the study, the environmental impacts of the pallets were compared on a one-trip basis and 100,000-trips basis, under nine impact categories chosen by researchers because of their environmental relevance. The categories included influence on ozone layer depletion, respiratory organics, aquatic ecotoxicity, terrestrial ecotoxicity, land occupation, aquatic acidification, aquatic eutrophication, global warming and non-renewable energy.

In findings published today (Feb. 3) in the Journal of Industrial Ecology, the researchers show that on a one-trip basis, wooden pallets treated with conventional kiln heating and as-yet novel, radio-frequency heat treatment incur an overall carbon footprint that is slightly lower than plastic pallets during their life cycle. For the 100,000-trips comparison, the differences are even more significant, they reported.

"It should be noted that wooden pallets that are heat-treated to kill pests incur a carbon footprint 20% to 30% lower than those treated with methyl bromide fumigation," Ray said. "Methyl bromide gas has been blamed for depleting the Earth's ozone layer. And theoretical calculations of the resource consumption and emissions of radio-frequency treatment of pallets suggest that the new dielectric technology may provide a lower-carbon alternative to both conventionally treated wooden pallets or plastic pallets."

Molded plastic pallets, typically, have a much longer life cycle than wooden pallets because plastic pallets are usually not broken or damaged and normally can travel more than 200 round trips before being taken out of service, Ray noted. Plastic pallets are made of sturdy, hardened material and are built to last longer. But they are typically derived from petroleum or natural gas products, which greatly increases their carbon footprint.

"What was lacking in this whole arena was a comprehensive life-cycle analysis, and that is what this study provides," Ray said. "More than a decade ago, other studies were commissioned by the wood pallet industry and by the plastic pallet industry, and of course those results favored the funders. This is the first academic, peer-reviewed study related to pallets, and it was funded entirely by Penn State and is unbiased."

With current concerns about climate change and in view of the massive amount of resources consumed to make many millions of pallets, assessing their carbon footprint is important, Ray believes. With 40 percent of all hardwood produced in the United States going into pallet production, he added, it is critical to know if wooden pallets are ecologically acceptable.

"Because I have worked my whole career in the wood products industry, I have gained a special appreciation for the benefits of wood as an environmentally friendly product," said Ray. "The topic interests me. It did not occur to me to do this research until the plastic pallet industry started talking about their products as environmentally superior. I questioned that statement and decided to do life-cycle analyses."

Also involved in the research were Sebastian Anil, now with Microsoft; Junfeng Ma, now with Mississippi State University; Gul Kremer, now with Iowa State University; and Shirin Shahidi, a graduate student in the Department of Ecosystem Science and Management when the research was conducted.

URBANA, Ill. - Alexander County sits near the confluence of the Mississippi and Ohio Rivers, at the southernmost tip of Illinois. The sparsely populated jurisdiction is perhaps best known for devastating floods resulting from repeated failures of the Len Small levee in 1993, 2011, and 2016. Homes and businesses have been severely damaged, residents stranded, and rich agricultural land irreversibly degraded by sand deposition and erosion.

Despite the severity of past flooding, the levee has been left unrepaired since 2016, leaving the area to flood every year since. Residents, land owners, county officials, and area lawmakers are clamoring for the U.S. Army Corps of Engineers to repair the breached levee. However, a new study led by a University of Illinois soil scientist predicts the levee will continue to fail even if repaired, and more extensive intervention is needed to prevent future flooding.

"Because the levee is built on unconsolidated ancient Ohio River valley alluvial sediments, which are easily eroded by the Mississippi River, any patch or repair will only be a short-term solution. The levee is very likely to fail again during a future major flooding event," says Kenneth Olson, professor emeritus in the Department of Natural Resources and Environmental Sciences at U of I.

In the study, Olson and co-author David Speidel, retired resource conservationist with the USDA Natural Resources Conservation Service, recount the re-alignment of the ancient and modern Mississippi River during the last 15,000 years.

Prior to the 1880s, the Mississippi River had multiple "relief valves" in the region. That is, when the river reached flood stage, excess water would naturally overtop river banks and flow into lowland areas like the Big Swamp, southwest of Cape Girardeau, Missouri. Olson and Speidel say shifting land use priorities, such as creating agricultural land by draining wetlands, spurred construction projects that dramatically changed the behavior of the river.

"Between 1880 and 1943, a diversion channel, embankment, and four levees were built in the area. They were designed to capture upland runoff, protect agricultural lands, and channel the river," Olson says. "But the levees cut off water storage areas that acted as relief valves at flood stage and significantly narrowed the river south of the Thebes Gap, increasing the volume, velocity, and water depth in the Mississippi River's main channel."

Compounding the problem, precipitation has increased 37% in the upper Midwest in the past 50 years. Olson says the convergence of fast-melting winter snowpack and high-precipitation events in the upper reaches of the river have increased runoff, exceeding the river channel's capacity.

As the Mississippi River snakes around Dogtooth Bend at the southern tip of Illinois, certain curved segments of the riverbank take the brunt of the river's erosive power. One of those spots, a section of the Len Small levee near Miller City, first failed in 1993. The breach was repaired that year, but the levee breached again in 2011 and 2016. In 2011, farmers patched it themselves, but the 2016 breach was too extensive for a do-it-yourself repair. The cost to fix it was an estimated $16 million, including a required $3-million local match. Without funds to make the necessary repairs, floodwaters now cross the Dogtooth Bend peninsula between river mile markers 33 and 15 every year.

Speidel says, "In the event a solution is not found and acted on to correct the 2016 levee breach, the agricultural land and roads on Dogtooth Bend peninsula will continue to degrade and the channel will continue to extend across the peninsula with each subsequent flooding event."

Navigation in the region has been impacted, as well. When floodwaters crossed the peninsula in 2019, six barges and multiple shipping lane markers got caught in the bypass flow. Eventually, the barges crossed the Miller City road, took out power lines, and finally came to rest on a farmer's irrigation system. Only four of the six barges could be removed before the floodwaters receded.

According to Olson, Dogtooth Bend farmers have been unable to produce crops during the last four growing seasons, and some have already sold their farm equipment. He says, "It is impossible for farmers to pay their farmland assessment tax bill without producing any crops. This degraded land needs an updated soil survey to assess the extent of soil damages, and degraded agricultural lands should now be taxed at a lower rate as either 'other land' or as 'conservation land.'

"As the frequency of intense precipitation events increase, the Illinois and Missouri levee systems are likely to fail repeatedly if maintained at their previous or current height, location, and strength. The current Army Corps solution - temporarily blocking the erosion with large rocks to prevent the navigation channel from moving - is not working in the Dogtooth Bend area," he adds. In fact, flooding has already started in 2020.

Olson and Speidel outline an alternate plan that acknowledges the current realities of the river, which seems determined to cut across the Dogtooth Bend peninsula. "Combinations of land use changes, a floodway bypass, expanded floodwater storage in the confluence area, and river training structures such as weirs, wing dikes, and step dikes are needed to address the flooding and maintain the existing Mississippi River shipping channel," Olson says.

More specifically, the plan calls for a wholesale shift in land use in the Dogtooth Bend peninsula area, from agriculture to wetlands, forest, wildlife habitat, and floodwater storage. "The current land owners will need to be compensated for any land use change," Olson asserts.

In addition, Olson and Speidel propose a new combined levee and causeway to keep the Miller City-to-Olive Branch road passable during flooding. They suggest the project could be funded from local and state highway funds in partnership with the Mississippi River Commission and the U.S. Army Corps of Engineers. The elevated causeway would further protect farmsteads and farmland that have not yet been degraded by past flooding events. Conservation easements are also being proposed for the degraded lands already affected by past flooding events.

In the past decade nanomedicine has contributed to better detection and treatment of cancer. Nanoparticles are several 100 times smaller than the smallest grain of sand and can therefore easily travel in the blood stream to reach the tumor. However, they are still too big to be removed by the kidneys. Since several doses of nanoparticles are necessary to treat a tumor, over time the nanoparticles can accumulate in the kidney and cause irreversible damage. In a study published in the scientific journal Biomaterials, materials scientists at the University of Freiburg led by Prof. Dr. Prasad Shastri from the Institute of Macromolecular Chemistry now present a natural solution to this problem: they built nanoparticles with the carbohydrate polysaccharides, which led to the excretion of the particles.

In nature viruses such as the herpes simplex virus-1 and the cytomegalovirus, which are able to pass through the kidney filtration apparatus despite their large size compared to nanoparticles. Shastri and his team identified that both viruses presents sugar molecules on their surface. Inspired by this observation, the scientists engineered nanoparticles containing polysaccharides. These carbohydrates are frequently found in the human tissue environment. Using a real-time imaging technique, which they have established in their laboratory, the team investigated in a mouse model the fate of these nanoparticles. They observed that the polysaccharide-enriched nanoparticles readily pass through the kidney and are excreted with the urine within a few hours after intravenous administration. The decisive factor for the researchers was that the nanoparticles continued to act as intended and were still able to target tumors.

"The ability to combine tumor accumulation and kidney clearance in the same nanoparticle represents a tipping point in ensuring that nanomedicines can be safely administered" says Shastri. "Our nature-inspired approach enabled us to trick the kidney environment to let nanoparticles pass through" adds Dr. Melika Sarem who was a co-author of the study.

WASHINGTON--A "beating heart" of frozen nitrogen controls Pluto's winds and may give rise to features on its surface, according to a new study.

Pluto's famous heart-shaped structure, named Tombaugh Regio, quickly became famous after NASA's New Horizons mission captured footage of the dwarf planet in 2015 and revealed it isn't the barren world scientists thought it was.

Now, new research shows Pluto's renowned nitrogen heart rules its atmospheric circulation. Uncovering how Pluto's atmosphere behaves provides scientists with another place to compare to our own planet. Such findings can pinpoint both similar and distinctive features between Earth and a dwarf planet billions of miles away.

Nitrogen gas - an element also found in air on Earth - comprises most of Pluto's thin atmosphere, along with small amounts of carbon monoxide and the greenhouse gas methane. Frozen nitrogen also covers part of Pluto's surface in the shape of a heart. During the day, a thin layer of this nitrogen ice warms and turns into vapor. At night, the vapor condenses and once again forms ice. Each sequence is like a heartbeat, pumping nitrogen winds around the dwarf planet.

New research in AGU's Journal of Geophysical Research: Planets suggests this cycle pushes Pluto's atmosphere to circulate in the opposite direction of its spin - a unique phenomenon called retro-rotation. As air whips close to the surface, it transports heat, grains of ice and haze particles to create dark wind streaks and plains across the north and northwestern regions.

"This highlights the fact that Pluto's atmosphere and winds - even if the density of the atmosphere is very low - can impact the surface," said Tanguy Bertrand, an astrophysicist and planetary scientist at NASA's Ames Research Center in California and the study's lead author.

Most of Pluto's nitrogen ice is confined to Tombaugh Regio. Its left "lobe" is a 1,000-kilometer (620-mile) ice sheet located in a 3-kilometer (1.9-mile) deep basin named Sputnik Planitia - an area that holds most of the dwarf planet's nitrogen ice because of its low elevation. The heart's right "lobe" is comprised of highlands and nitrogen-rich glaciers that extend into the basin.

"Before New Horizons, everyone thought Pluto was going to be a netball - completely flat, almost no diversity," Bertrand said. "But it's completely different. It has a lot of different landscapes and we are trying to understand what's going on there."

Western winds

Bertrand and his colleagues set out to determine how circulating air - which is 100,000 times thinner than that of Earth's - might shape features on the surface. The team pulled data from New Horizons' 2015 flyby to depict Pluto's topography and its blankets of nitrogen ice. They then simulated the nitrogen cycle with a weather forecast model and assessed how winds blew across the surface.

The group discovered Pluto's winds above 4 kilometers (2.5 miles) blow to the west -- the opposite direction from the dwarf planet's eastern spin -- in a retro-rotation during most of its year. As nitrogen within Tombaugh Regio vaporizes in the north and becomes ice in the south, its movement triggers westward winds, according to the new study. No other place in the solar system has such an atmosphere, except perhaps Neptune's moon Triton.

The researchers also found a strong current of fast-moving, near-surface air along the western boundary of the Sputnik Planitia basin. The airflow is like wind patterns on Earth, such as the Kuroshio along the eastern edge of Asia. Atmospheric nitrogen condensing into ice drives this wind pattern, according to the new findings. Sputnik Planitia's high cliffs trap the cold air inside the basin, where it circulates and becomes stronger as it passes through the western region.

The intense western boundary current's existence excited Candice Hansen-Koharcheck, a planetary scientist with the Planetary Science Institute in Tucson, Arizona who wasn't involved with the new study.

"It's very much the kind of thing that's due to the topography or specifics of the setting," she said. "I'm impressed that Pluto's models have advanced to the point that you can talk about regional weather."

On the broader scale, Hansen-Koharcheck thought the new study was intriguing. "This whole concept of Pluto's beating heart is a wonderful way of thinking about it," she added.

These wind patterns stemming from Pluto's nitrogen heart may explain why it hosts dark plains and wind streaks to the west of Sputnik Planitia. Winds could transport heat--which would warm the surface--or could erode and darken the ice by transporting and depositing haze particles. If winds on the dwarf planet swirled in a different direction, its landscapes might look completely different.

"Sputnik Planitia may be as important for Pluto's climate as the ocean is for Earth's climate," Bertrand said. "If you remove Sputnik Planitia - if you remove the heart of Pluto - you won't have the same circulation," he added.

The new findings allow researchers to explore an exotic world's atmosphere and compare what they discover with what they know about Earth. The new study also shines light on an object 6 billion kilometers (3.7 billion miles) away from the sun, with a heart that captivated audiences around the globe.

"Pluto has some mystery for everybody," Bertrand said.

Plant cells tend to grow longer instead of wider due to the alignment of the many layers of cellulose that make up their cell walls, according to a new study that may have implications for biofuels research. The study, which appears online Feb. 4 in the Journal of Experimental Botany, reveals that the protein CSI1 and the alternating angle of the cell wall's layers, creating a herringbone pattern, are critical for cell growth.

"When plant cells grow, they tend to expand considerably along their length while not increasing much in width," said Ying Gu, associate professor of biochemistry and molecular biology and co-funded faculty member in the Institutes of Energy and the Environment at Penn State and lead author of the study. "It is generally thought that microtubules--structures that form the "skeleton" of the cell--wrap around the cell like rings on a barrel, restricting growth in width. We wanted to know what regulates growth in the cell's length, and found that the story is more complicated than just rings on a barrel."

The team first confirmed that a protein they had previously identified as important to the creation of cellulose--the main component of cell walls--is also important to cell growth. A mutant form of the model species thale cress, Arabidopsis thaliana, without the protein known as "cellulose synthase interactive 1" (CSI1) showed severely reduced growth, even in the presence of a growth hormone. A follow-up test indicated that this reduced growth may be due to changes to the mutant's cell wall.

"On a whim, one of my graduate students decided to perform a creep test, where plant cells are stretched out under acidic conditions," said Gu. "Acidic conditions usually instigate cell growth, but the mutant lacking CSI1 didn't elongate during the test. This suggested that the issue may be with the cell wall or the cell architecture, which was a surprise."

Plant cell walls are composed of many layers, 10 to 20 in thale cress and 50 to 100 in many other species. Each layer is composed of proteins as well as cellulose microfibers, which are deposited by the cellulose synthase complex, with help from CSI1, as the complex follows along a microtubule. The microfibers in a given layer are deposited at about a 60-degree angle compared to the microfibers in the previous layer. The alternating angles of microfibers in each layer create a herringbone pattern and produce what scientists call crossed-polylamellate walls.

"CSI1 acts as a linker protein, helping the cellulose synthase complex deposit microfibers," said Gu. "We thought that without CSI1, microfibers in the mutant would be deposited in random orientations. Instead, we found that the microfibers in each layer were all deposited in the same direction, which was a huge surprise."

The researchers then pharmacologically disrupted the herringbone pattern in a normal plant's cell walls, which prevented cells from growing normally even in the presence of a growth hormone. These results suggest that crossed-polylamellate walls are integral to cell growth in plants.

"It's possible that CSI1 helps initiate the change in angle between layers," said Gu. "We plan to investigate this hypothesis in the future."

Based on their study, the researchers believe that CSI1 and the crossed-polylamellate wall structure are critical to the elongation of cells and suggest that existing theories about cell growth--as well as the analogy of rings on a barrel--are incomplete. Improving understanding of how plant cells build cellulose and cell walls could eventually help scientists more easily break it apart for use in biofuels.

GRAND RAPIDS, Mich. (Feb. 4, 2020) -- Significantly reducing dietary levels of the amino acid methionine could slow onset and progression of inflammatory and autoimmune disorders such as multiple sclerosis in high-risk individuals, according to findings published today in Cell Metabolism.

While many cell types in the body produce methionine, the immune cells responsible for responding to threats like pathogens do not. Instead, the methionine that fuels these specialized cells, called T cells, must be ingested through food consumption. Although methionine is found in most foods, animal products such as meat and eggs contain particularly high levels.

"Methionine is critical for a healthy immune system. Our results suggest, for people predisposed to inflammatory and autoimmune disorders like multiple sclerosis, reducing methionine intake can actually dampen the immune cells that cause disease, leading to better outcomes" said Russell Jones, Ph.D., the study's senior author and program leader of Van Andel Institute's Metabolic and Nutritional Programming group. "These findings provide further basis for dietary interventions as future treatments for these disorders."

Autoimmune disorders occur when the immune system mistakenly attacks and destroys healthy tissue. For example, in multiple sclerosis -- the most common inflammatory disease of the central nervous system -- the myelin sheath that protects nerve cells in the brain and spinal cord is targeted by the immune system. The subsequent damage impedes messages traveling to and from the brain, resulting in progressively worsening symptoms like numbness, muscle weakness, coordination and balance problems, and cognitive decline. There currently are no treatments that significantly slow or stop multiple sclerosis without greatly increasing the risk of infection or cancer.

"What causes multiple sclerosis is still not completely understood. We know that genes related to the immune system are implicated but environmental factors also have a role to play," said Catherine Larochelle, M.D., Ph.D., study co-author, and a clinician-scientist in neuroimmunology and neurologist at the Multiple Sclerosis Clinic at the Centre Hospitalier de l'Université de Montréal. "The fact that metabolic factors like obesity increase the risk of developing multiple sclerosis makes the idea of dietary intervention to calm down the immune system particularly appealing."

During an immune response, T cells flood the affected area to help the body fend off pathogens. Jones, Larochelle and their teams found dietary methionine fuels this process by helping "reprogram" T cells to respond to the threat by more quickly replicating and differentiating into specialized subtypes. Some of these reprogrammed T cells cause inflammation, which is a normal part of an immune response but can cause damage if it lingers, such as the nerve damage that occurs in multiple sclerosis.

The researchers also found that significantly reducing methionine in the diets of mouse models of multiple sclerosis altered the reprogramming of T cells, limiting their ability to cause inflammation in the brain and spinal cord. The result was a delay in the disease's onset and slowed progression.

"By restricting methionine in the diet, you're essentially removing the fuel for this over-active inflammatory response without compromising the rest of the immune system," Jones said.

He cautions that the findings must be verified in humans before dietary guidelines can be developed. The team also plans to investigate whether new medications can be designed that target methionine metabolism.

The study is the latest to spotlight methionine-restricted diets as possible treatments for disease. A 2019 study from the Locasale Lab at Duke University demonstrated that reducing methionine could improve the effects of chemotherapy and radiation in fighting cancer.

New Haven, Conn. -- In a pair of related studies, a team of Yale researchers has found a way to reverse type-2 diabetes and liver fibrosis in mice, and has shown that the underlying processes are conserved in humans.

The studies appear in the Feb. 4 edition of Cell Reports and in the Jan. 17 edition of Nature Communications.

In the earlier study, researchers found an important connection between how the body responds to fasting and type-2 diabetes. Fasting "switches on" a process in the body in which two particular proteins, TET3 and HNF4?? increase in the liver, driving up production of blood glucose. In type-2 diabetes, this "switch" fails to turn off when fasting ends, as it would in a non-diabetic person.

Researchers hypothesized that if they could "knock down" the levels of these two proteins, they could stop diabetes from developing. Huang and team injected mice with genetic material known as small interfering RNAs (siRNAs) packaged inside viruses that targeted TET3 or HNF4?. They found that blood glucose and insulin dropped significantly -- effectively stopping diabetes in its tracks.

In the Feb. 4 Cell Reports study, researchers looked at how TET3 contributed to the development of fibrosis in the liver, and found that the protein was involved in fibrosis on multiple levels. Almost all fibrosis, regardless of the organ involved, starts from abnormal protein signaling, Huang said.

She and colleagues discovered that TET3 plays a role in the fibrosis signaling pathway in three different locations -- and acts as an important regulator in fibrosis development. This means there are likely opportunities to develop drugs that inhibit TET3 to slow or reverse fibrosis, said Da Li, associate research scientist in genetics and co-author on both studies.

Both diseases -- type-2 diabetes and fibrosis of the liver and other organs -- are common, but have few treatment options. Around 28 million people in the U.S. have type-2 diabetes, characterized by high blood sugar levels, a condition that can lead to many other health problems, including heart disease, stroke, and kidney failure.

Cirrhosis is one of the leading causes of death worldwide and is marked by liver fibrosis -- a buildup of scar tissue on the liver, said co-author James Boyer, M.D., professor and emeritus director of the Yale Liver Center.

Researchers noted that several drugs, such as metformin, are currently available to control blood sugar levels in patients with diabetes. But these have a range of unpleasant side effects, and patients can develop resistance to these drugs.

And there is little medical relief for fibrosis sufferers.

"Right now, there are no effective drugs for the treatment of fibrosis," said Xuchen Zhang, M.D., associate professor in pathology and co-author on the fibrosis study.

Huang has filed for a patent related to her discoveries with support from the Yale Office of Cooperative Research.

The next step, she said, will be to identify where to best target TET3 and HNF4??and to develop the most effective siRNAs or small molecules to treat type-2 diabetes or fibrosis.

Infectious disease researchers at The University of Texas at Austin and other institutions in Hong Kong, mainland China and France have concluded there is a high probability that the deadly Wuhan coronavirus spread beyond Wuhan and other quarantined cities before Chinese officials were able to put a quarantine in place. At least 128 cities in China outside of the quarantine zone, including cities with no reported cases to date, had a greater than even risk of exposure, according to a paper currently in press with Emerging Infectious Diseases, a journal of the U.S. Centers for Disease Control and Prevention.

Based on comprehensive travel data from location-based services and modeling of the disease done at UT Austin's Texas Advanced Computing Center, 128 cities in China had a 50% chance or greater risk that someone exposed to the virus traveled there before the quarantine began. The team also estimated there were 11,213 cases of the coronavirus in Wuhan by the time of the quarantine on Jan. 22 -- a rate 10 times higher than the reported cases.

"This risk assessment identified several cities throughout China likely to be harboring yet undetected cases of [Wuhan coronavirus] and suggests that early 2020 ground and rail travel seeded cases far beyond the Wuhan region quarantine," write the authors.

As of Feb. 4, officials have confirmed 425 fatalities from the virus, all but two in mainland China, and more than 20,000 confirmed cases spread across the world.

The paper shows there is a 99% chance that at least one patient carrying the virus traveled to the cities of Beijing, Guangzhou, Shenzhen and Shanghai by the time the quarantine was put in place for the city of Wuhan on Jan. 23. The quarantine has since expanded to include cities with populations totaling 60 million people. Beijing reported its first fatality from the virus on Jan. 27.

The team estimated new cases of the virus doubled roughly every week, and on average, that every infected person transmitted the disease to approximately two other people.

Lauren Ancel Meyers, a mathematical epidemiologist and professor of integrative biology and statistics and data sciences at UT Austin; and Zhanwei Du, a computer scientist working at UT Austin, along with a team of scientists from France, China and Hong Kong, used historical travel data for the busy Spring Festival season to chart human movements between 371 cities in China. The team used road, train and air travel data to yield results more accurate than those of other models.

"Given that 98% of all trips during this period are taken by train or car, our analysis of air, rail and road travel data yields more granular risk estimates than possible with air passenger data alone," said Meyers, who specializes in modeling the spread of infectious diseases. "The quarantine will probably prevent future transmission out of Wuhan. However, introductions of the novel coronavirus had already occurred throughout China and the world by the time the quarantine started."

The model also takes into account the reported cases of the disease outside of China to estimate the rates of epidemic growth.

Based on the team's estimates, there are at least 128 cities and as many as 186 cities in China that had at least a 50% chance of an infected visitor from Wuhan arriving sometime in the three weeks before the quarantine was enacted. Several cities reporting no cases had a 99% probability that an infected person visited. Those cities -- each with a population of more than 2 million people -- include Fushun, Laibin and Chuxiong.

Washington, DC-- A new approach to analyzing seismic data reveals deep vertical zones of low seismic velocity in the plumbing system underlying Alaska's Cleveland volcano, one of the most-active of the more than 70 Aleutian volcanoes. The findings are published in Scientific Reports by Helen Janiszewski, recently of Carnegie, now at the University of Hawai?i at Mānoa, and Carnegie's Lara Wagner and Diana Roman.

Arc volcanoes like Cleveland form over plate boundaries where one tectonic plate slides beneath another. They are linked to the Earth's mantle by complex subsurface structures that cross the full thickness of the planet's crust. These structures are more complex than the large chambers of molten rock that resemble a textbook illustration of a volcano. Rather, they comprise an interlaced array of solid rock and a "mushy" mix of partially molten rock and solid crystals.

Resolving this subterranean architecture is crucial for emergency planning and saving human lives. But these regions have been difficult to image.

Since it's impossible for humans to directly observe the depths of our planet's interior, scientists need instruments to help them visualize what's happening down there. Traditionally, a variety of geophysical and geochemical approaches are deployed to determine the structures that exist beneath a volcano.

For example, the seismic waves caused by earthquakes can be used like an ultrasound to map the Earth's interior. But for this to work, the waves must reach the subterranean structures that the scientists want to study. Although Cleveland has frequent gas emissions, explosions, and ash deposits at its surface, there is very little evidence of seismic activity deep beneath the volcano. This makes imaging the architecture of the lower and middle crust below Cleveland very challenging.

Until now, the number of instruments needed to use seismic waves traveling from more-distant earthquakes for imaging was prohibitive.

In this work, Janiszewski demonstrated a novel technique that uses seismic waves coming from distant earthquakes but isolates just the part of them that is affected by moving through the boundary between the Earth's mantle and crust. This allowed Janiszewski to build models that better distinguish the partially molten regions from the surrounding solid rock in these difficult-to-reach depths beneath Cleveland volcano without requiring a much-more-extensive number of seismic stations at the surface.

"We revealed the volcano's deep subterranean structure in never-before-seen detail, using fewer instruments by an order of magnitude than is typical for detailed seismic imaging at volcanoes," Janiszewski said.

Unlike typical seismic imaging experiments that deploy dozens of seismometers, this study used only eight. Six of these stations were deployed as part of the NSF-funded Islands of the Four Mountains experiment between August 2015 and July 2016. Two were permanent Alaska Volcano Observatory stations.

"The technique will allow imaging of structures underneath volcanoes where there are only a few stations, or where a lack of deep earthquakes in the vicinity makes other methods difficult," Janiszewski added.

A new study in Burns & Trauma, published by Oxford University Press, reveals promising new strategies to prevent skin scarring after injuries.

While scars are common when wounds heal, hypertrophic scarring is a skin condition characterized by deposits of excessive amounts of collagen. This results in a thick and often raised scar. The underlying mechanisms of hypertrophic scar development are poorly understood, however. The Burns & Trauma paper reviewed strategies for treating hypertrophic scars.

Skin wound healing is a process that consists of three phases: inflammation, proliferation, and regeneration. Hypertrophic scar formation can occur as a result of an abnormality in these processes. The frequency of such scarring ranges from 40% to 94% following surgery and from 30% to 91% following a burn injury. In poorer countries, the incidence rate is greater reflecting the high rate of burn injuries.

Major risk factors for hypertrophic scar formation include gender, age, genetic predisposition, wound size and depth, anatomical site, and mechanical tension on the wound. Such scarring hinders normal function, and obviously results serious physical, psychological, and aesthetic problems for patients.

It is widely accepted that the time to complete wound healing is the most important factor to predict the development of hypertrophic scars. Only one-third of wounds developed scarring tissue if healing occurred between 14 and 21 days. Some 78% of the sites resulted in serious scarring if the wound healed after 21 days.

The established therapies for preventing serious skin scarring include pressure therapy, which has long been considered the mainstay non-invasive treatment for hypertrophic scarring. It is widely used worldwide and its effectiveness has been established. It's likely more effective suggested that it is more effective if pressure therapy is performed within two months after the initial injury.

Other interventions include silicone, steroids, and laser therapy. While the effectiveness of silicone therapy has not been completely determined, the topical administration of steroids for burn injuries has been generally used and reported to be effective. There is consistent evidence that early laser intervention for the prevention would be beneficial in both the speed of scar reduction and the efficacy of therapeutic response.

Resection (cutting out the tissue) and radiation can often be used in addition to the primary therapies. Surgical approaches do, however, vary with the type of scar. Researchers involved with this paper argue that we need long term results in order to make decisions about using resection or radiation as a medical intervention.

The drug botulinum toxin A (btxA) is widely used for cosmetic purposes, as well as treating headaches and other pain. It is also often used to treat hypertrophic scars. Researchers involved in this paper emphasize that while btxA appears to have some positive effect on scar prevention, researchers still haven't decided on the optimal concentration of the drug to treat scarring. It may depend on the size or severity of the wound. They conclude the drug is promising and worth investigating further.

Future management possibilities for hypertrophic scar therapy include anti-angiogenesis therapy, which inhibits the development of new blood vessels, fat grafting, and stem cell therapy. There are several experimental investigations on the effectiveness such therapies to reduce abnormal tissue formation.

MEDFORD/SOMERVILLE, Mass. (February 4, 2020)-- Researchers led by biologists at Tufts University have discovered that the brains of developing embryos provide signals to a nascent immune system that help it ward off infections and significantly improve the embryo's ability to survive a bacterial challenge. Using frog embryos, which continue to develop with their brains removed, the researchers found that embryos without a brain are not able to marshall the forces of immune cells to an injury or infection site, leading the embryo to succumb to an infection more quickly. By contrast, the presence of a brain crucially helps direct immune cells to the site of injury to overcome the bacterial threat. The study was published today in NPJ Regenerative Medicine.

In a developing embryo, both brain and immune system are not fully formed. The immune system, for its part, consists mostly of an "innate" system of cells that respond immediately to infection and do not require training or produce antibodies. Nevertheless, these cells require signals that prompt them to move toward an infection site and trigger a response.

The research team found that the brain appears to contribute to the signals that guide the nascent immune system. When brainless frog embryos were infected with E. coli, only about 16% of embryos survived, while the presence of a brain protected more than 50% from the infection. By following markers of immune cells, researchers confirmed that the effect is not due to the missing brain somehow hampering immune system development because the composition of the immune cells remained the same with or without a brain. Instead, they found that the effect was due to the brain sending signals to the immune cells to move toward the site of an infection.

"We found that macrophages -innate immune system cells that can swallow up bacteria and destroy them to reduce the burden of an infection do not migrate appropriately without the presence of the brain" said Michael Levin, Vannevar Bush Professor of Biology at Tufts University's School or Arts and Sciences and Associate Faculty at Harvard's Wyss Institute, director of the Allen Discovery Center at Tufts and corresponding author of the study. "Without the brain and its neurotransmitter signals, gene expression and innate immune system activity go awry, resulting in increased susceptibility to bacterial pathogens. "

Other roles for the embryonic brain signaling during infection may include inducing cellular responses, for example preventing cell death or reducing inflammation, that help protect against the harmful effects of the infection.

Immune system abberations were also observed in brainless embryos that were further developed. When the researchers tracked myeloid cells, a class of immune cells that includes macrophages, neutrophils and others, after an injury, they found that the myeloid cells in brainless embryos gathered in locations far from the injury site. By contrast, myeloid cells in normal embryos with intact brains would pile up at the injury site to assist in healing. In fact, in the brainless embryo, the myeloid cells tended to cluster around abnormal, disorganized peripheral nerve networks, also a by-product of brain absence, as demonstrated in earlier studies.

An examination of aberrations in genetic expression in brainless embryos also pointed to the reduction of the neurotransmitter dopamine (a signaling chemical used in the brain for learning and motivation), and that dopamine may play a role in activating immune cells to migrate in the early stages of an infection. The absence of an immune cell quorum at the infection site leads the brainless embryos to become more susectible to its lethal effects.

"Our results demonstrate the deep interconnections within the bacteria-brain-body axis: the early brain is able to 'sense' the pathogenic bacteria and to elaborate a response targeted to fight against the cellular and molecular consequences of the infection," said Celia Herrera Rincon, Research Scientist II at the Allen Discovery Center at Tufts, and first author of the study.

It may not always seem so, but scientists are convinced that humans are unusually cooperative. Unlike other animals, we cooperate not just with kith and kin, but also with genetically unrelated strangers. Consider how often we rely on the good behavior of acquaintances and strangers-- from the life-saving services of firefighters and nurses, to mundane activities like our morning commute and queueing at the airport check-in counter. Of course, we encounter people who cheat, disregard the welfare of others, and engage in cronyism and nepotism. But we tend to perceive these behaviors as deviant, whereas in most animal societies these behaviors are the gold standard.

The hotly contested issue is why we are the famed cooperators of the animal kingdom. The answer is thought to be some characteristic that is exaggerated in humans compared to other animals: language, intelligence, culture, large-game hunting, or our very needy children. Teasing apart how these traits influenced the evolution of cooperation has been challenging and has led to a proliferation of theories--and acrimonious debates--that emphasize one or other of these characteristics.

A study by ASU researchers Carla Handley and Sarah Mathew published in Nature Communications provides some insight on this issue by pinpointing how culture may have fueled our capacity to cooperate with strangers. The researchers empirically tested--and confirmed--predictions of a controversial theory referred to as cultural group selection theory. The idea is that culturally different groups compete, causing the spread of traits that give groups a competitive edge. Cooperation is exactly such a trait--costly for individuals, but advantageous for groups. Handley was a postdoctoral researcher with Arizona State University at the time of study, and Mathew is assistant professor in the ASU School of Human Evolution and Social Change and research affiliate with the Institute of Human Origins.

During the second half of the 20th century, biologists famously discredited the idea that selection could act on groups. They found that, typically, groups are not different enough from each other for selection to act on. Because individuals migrate, over time migration makes the composition of groups similar. Group-beneficial behaviors like cooperation therefore lose out.

The above concern may not apply, however, for behaviors that are culturally, rather than genetically, transmitted. When people migrate, they can, through social learning, culturally acquire the behaviors that are popular in their new surrounding. Thus, cultural groups can remain different, even if people move a lot. This means that selection can act on groups, and group-beneficial behaviors like cooperation can flourish.

"People have the intuition that being cultural helps us cooperate. What we are showing is that culture allows groups to be different, and therefore to compete. It is this group competition--ironically--that sculpted our cooperativity," said Mathew.

To evaluate this theory, Handley and Mathew examined cultural variation and cooperation among Kenyan pastoralists. They sampled 759 individuals from nine clans spanning four ethnic groups--the Borana, Rendille, Samburu and Turkana--all of who practice semi-nomadic subsistence pastoralism in the arid savanna of northern Kenya. These groups compete intensively among each other for pasture, dry-season water wells and livestock, including through lethal cattle raids. The researchers found that, as predicted, cultural practices and beliefs were substantially variable between populations. Ten to 20 percent of the observed cultural variation was between competing groups. In contrast, typically less one percent of genetic variation is between groups. This indicated that there is potential for cultural group selection to occur.

Next, they examined who people cooperate with and found that cooperation is indeed directed towards cultural ingroup members. People feel obliged to cooperate with strangers, as long as they share their cultural values, beliefs and norms with those people. Such culturally parochial cooperation is to be expected if competition between cultural groups influenced the evolution of cooperation.

"This study is unique as an empirical field test of cultural group selection by examining how cooperation operates between and within four distinct ethnolinguistic groups," said Handley. "Taking a step back, it may also contribute to a reframing of conflict discourse in small-scale societies where cooperative action has been severely underrepresented and 'illegitimate' violence is regarded as the status quo."

The findings caution that although humans are hyper cooperative, our evolved cooperative dispositions are still limited in their scale, thus proving challenging for solving global-scale problems. Innovative thinking is necessary if we are to save ourselves from climate change, pandemics, and of course, aliens.

BINGHAMTON, N.Y. ? Publicly sharing a goal may help you persist after hitting a failure, but only if you care about what others think of you, according to new research from Binghamton University, State University of New York.

However, public announcements, such as Facebook posts about New Year's resolutions or weight loss targets, may only be motivating when there is immediate feedback after a failure and if there is a high incentive in reaching a goal.

"Everyone sets goals, and some people choose to make those goals public instead of keeping them private. Everyone also fails to meet goals from time to time," says Jenny Jiao, an assistant professor of marketing at Binghamton University's School of Management. "We were interested in finding out what happens after a failure."

Working with Catherine Cole, a professor of marketing at the University of Iowa's Tippie College of Business, Jiao studied the effects of goal publicity, failure feedback and goal incentives on goal persistence across three different studies.

Each study consisted of subjects completing a task, learning they failed, and giving them another opportunity to complete the task, with variations to control for each of the effects they wanted to test.

"When you hit a failure, virtually all of the effort you've put into your goal is now a sunk cost. You can't go back and try to fix what you've already done. You now only have two options - give up or keep trying," says Jiao.

The effect of goal publicity

Researchers found that publicly announcing your goal only affects those who care about what others think about them.

"If your public reputation is something you hold in high regard, then failing publicly is probably going to push you to not want to fail publicly again. There is a greater chance you're going to try hitting that goal again." says Jiao. 

However, Jiao says people who do not care too much about public perception aren't affected by the public or private nature of a goal after hitting failure.

"If you don't care as much about your reputation, then it's not going to matter if people know about your failure or not," she says. "If they think you are a failure, that is not going to bother you as much."

The effect of failure feedback

Researchers found that feedback plays an important role in goal persistence after a failure.

Jiao says those who receive feedback immediately after a failure are more likely to continue pursuing a goal than those who receive no feedback or delayed feedback.

"If someone gives you immediate feedback, you then start thinking about what you could've done better," says Jiao. "If that feedback is delayed, then you've probably found ways to justify your failure, and you're less likely to pick your goal back up."

The effect of incentives

Researchers found that incentives need to be perceived as high for someone to continue working towards a goal after hitting a failure.

"You may reassess a goal after failing and realize that it may not be worth the effort," says Jiao. "However, if there is a reward that you perceive as being very valuable, it's going to keep pushing you towards reaching that goal."

As a marketing researcher, Jiao's hopes the study will help marketers understand what drives consumers to keep working towards a goal after hitting a failure. She says the implications could help companies understand how to structure rewards programs or loyalty cards.

"Some companies spend millions on marketing campaigns that encourage consumers to post goals on social media. This research shows that it's only effective for certain kinds of consumers," says Jiao. "It also shows the importance of immediate feedback and incentives if you want consumers to continue working towards those goals."

To address the receptor dysfunction associated with several serious neurological diseases, Michaela Jansen, Pharm.D., Ph.D., from the Texas Tech University Health Sciences Center School of Medicine recently completed a study that provides novel insights into a protein-protein interaction that may one day lead to more effective treatments for these disorders. The study, "Delineating the site of interaction of the 5-HT3A receptor with the chaperone protein RIC-3," was recently published in Biophysical Journal.

Serotonin type 3A (5-HT3A) is a member of the protein superfamily known as pentameric ligand-gated ion channels (pLGIC). These channels, primarily located within the central and peripheral nervous systems, act as neurotransmitter receptors, a type of receptor that binds with neurotransmitters rather than other molecules and produces an electrical signal by managing ion channel activity. When they don't function properly, these proteins have been linked to Alzheimer's disease, Parkinson's disease, epilepsy, schizophrenia, alcohol addiction and myasthenia gravis, a chronic autoimmune disease that causes certain muscles to weaken.

Members of the pLGIC superfamily are assembled from five subunits, each of which consists of three domains: the extracellular domain (ECD), the transmembrane domain (TMD) and the intracellular domain (ICD).

In previous research, Jansen and her team showed that the ICD of 5-HT3A interacts with a chaperone protein known as Resistance to Inhibitors of Cholinesterase 3 (RIC-3). Chaperone proteins like RIC-3 help the subunits of pLGIC proteins, like 5-HT3A, assemble and function properly.

"For this study, we specifically looked at the serotonin-gated ion channel; it's a good model system because you have five times the same subunit within one channel, which makes it somewhat easier to study" Jansen said. "Clinically, it's important for drugs that, for example, are used to treat very severe nausea and vomiting during cancer treatment with chemotherapeutic agents. So we use this receptor a lot as a model system."

The ICD for 5-HT3A consists of 115 amino acids linked together in a peptide chain. Though her team had demonstrated previously that the ICD is required and sufficient for the chaperone protein to act, they didn't know which segment of amino acids along the ICD chain supported the interaction between the receptor protein 5-HT3A and the RIC-3 chaperone protein.

"With this study, we show that the very first segment, which consists of 24 amino acids, is essentially all that's needed for the interaction," Jansen said. "Interestingly, this segment contains a short alpha helix that we think is conserved across other members of the ion channel super family, so this will help us to apply what we learned here to several related channels."

Specifically, Jansen said, her team investigated which sites of the 5-HT3A and the RIC-3 have to fit together so that the machinery that leads to assembly can work. This is important because the number of receptors in the brain is disturbed in some diseases.

For example, many times the number of channels is altered for Alzheimer's disease, so understanding how this protein-protein assembly works could help researchers design drugs that mimic the interaction. Jansen believes this could help, in a pharmacological way, to correct the receptor numbers in the brain.

"This is important because if you know this part, and the structure of it is known, then you could say, 'OK, let's make a drug that binds to the surface of the segment,'" Jansen said. "This can help us with regulating receptor numbers for Alzheimer's disease; you have the lock, now you can design the key for it because you know the structure of this segment. This is what is needed for structure-guided drug design; you can conceptualize a small drug-like molecule and then investigate if that works to interfere with processes that are not functioning in certain disease states."

Having narrowed down the important role 5-HT3A plays in this protein-protein interaction, Jansen and her team will go back and similarly investigate RIC-3.

"When we do that, we'll more fully understand the two detailed parts that need to interact," Jansen said. "I think that would complement this study and be a good step forward."