Culture

How tiny enzymes reign supreme in worldwide carbon recycling

image: White rot fungi, Duke Forest, North Carolina

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The recycling of most of the carbon in nature depends on the breakdown of two polymers in woody matter, notably cellulose and lignin. In a paper just published in the journal Biochemistry, Richard Wolfenden, PhD, and colleague Charles Lewis, PhD, both in the UNC Department of Biochemistry and Biophysics, show the extent to which enzymes from woodland fungi accelerate the breakdown of lignin, a complex polymer held together entirely by ether linkages.

After a tree falls in the forest and the chain saw has done its work, clusters of white-rot fungi appear near the cut surfaces. "Etherases" from these lowly fungi use the antioxidant glutathione to clip ether linkages in 23 milliseconds. Lewis and Wolfenden show that without these enzymes, the half-life for the needed hydrolysis of the ether linkages in lignin in water would be about 100 billion years, exceeding the age of the universe by a long shot.

So it turns out that these familiar organisms catalyze what is generally considered to be the rate-determining step in the global carbon cycle, using enzymes that are found to achieve the largest rate enhancement known for any of the thousands of enzymes that exist.

Without these little enzymes, we'd be in a world of hurt.

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University of North Carolina Health Care

Depression affects one-third of lung cancer patients

COLUMBUS, Ohio - About one-third of patients newly diagnosed with the most common form of lung cancer have moderate to severe symptoms of depression, a new study suggests.

For many of these patients -- particularly those with severe symptoms -- depression occurs in a toxic blend of high levels of anxiety, traumatic stress, impaired day-to-day functioning and significant pain and other physical symptoms, findings showed.

The results suggest doctors need to screen lung cancer patients for depression and then act to refer patients for care, said Barbara Andersen, lead author of the study and professor of psychology at The Ohio State University.

"Some oncologists may have a mindset that 'of course, you're depressed, you have lung cancer.' This may show an under-appreciation of the breadth of depressive symptoms and other difficulties which accompany it," Andersen said.

Patients with moderate or severe depressive symptoms are more likely to have lower quality of life and worse disease outcomes compared to those also diagnosed with lung cancer but with mild or no depressive symptoms.

"This is more than having a 'low mood.' When severe, the depression rarely gets better without treatment," she said.

The study, published online in the journal Lung Cancer, also included Ohio State psychology students and researchers from Ohio State's Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Data came from 186 patients at one cancer hospital who had been recently diagnosed with advanced-stage non-small cell lung cancer, which accounts for 85 percent of all lung cancer cases.

Patients completed a telephone survey measuring psychological and physical symptoms, stress and day-to-day functioning.

Results showed that 8 percent of the patients scored at the severe depressive symptom level and 28 percent had moderate depressive symptoms.

Nearly all (93 percent) of the patients with severe depression said the depressive symptoms made it difficult to do their work, take care of things at home and get along with other people.

They reported high levels of hopelessness, and one-third of those with severe depressive symptoms reported thoughts of suicide. They had extreme levels of cancer-related stress, and the least confidence that their cancer treatment would help.

Compared to other cancer patients, those with high levels of depressive symptoms were much more likely to report severe physical symptoms, including 73 percent who said they experienced "quite a bit" or "very much" pain.

Every one of the patients with severe depressive symptoms said they had severe or moderate issues functioning with their usual activities such as work, study, housework and family or leisure activities.

"Depression is just part of what these patients are dealing with. It comes with this whole package of worse functioning, more physical symptoms, stress, anxiety and more," Andersen said.

"All of these can have negative effects on treatment, overall health, quality of life and disease progression."

In general, those with moderate depressive symptoms saw negative effects that were somewhat less -- but still significant -- than those with severe symptoms, the study found.

But there were two striking differences between the groups.

One was in the severity of generalized anxiety disorder (or GAD) symptoms, the most common anxiety disorder. About 11 percent of those with moderate depressive symptoms had moderate to severe GAD, compared to 73 percent of patients with severe depressive symptoms.

"GAD worry or fear can be particularly toxic for lung cancer patients. It can impede decision-making and participation in treatment. Moreover, a common symptom of lung cancer, shortness of breath, can worsen with anxiety and even induce panic for some," Andersen said.

Second, many fewer of the patients with moderate depressive symptoms had impairments in self care (8 percent versus 33 percent in those with severe depressive symptoms), mobility (33 percent versus 73 percent) and usual activities (38 percent versus 100 percent).

Andersen said she was also struck by the "extraordinarily" high levels of cancer-specific stress reported by those with severe depressive symptoms. The levels exceeded the cutoff for likely diagnosis of post-traumatic stress disorder. Andersen said she could not find any other studies of cancer patients with stress levels as high as those for the patients with severe depressive symptoms.

Patients in this study are being followed to provide longitudinal data on their psychological responses and outcomes, including survival.

Andersen said she expects links will be found between depressive symptoms and survival. In previous research, she and her colleagues have found that depression was linked to lower survival rates in breast cancer patients -- but that mental health treatment helped them.

"We need depression to be taken more seriously in lung cancer patients. Because the patients in this research were screened as part of study participation, their physicians were notified of their need for further evaluation and treatment," she said.

"New therapies, targeted and immunotherapy, are significantly improving outcomes. Patients are living longer, and we need to make similar efforts and advancements to treat symptoms such as these and help patients maintain their quality of life going forward," she said.

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Ohio State University

Silverswords may be gone with the wind

Silversword plants of Hawai'i - known by their Hawai'ian name 'ahinahina which translates to very grey - are unique to the Maui's Haleakalā volcano summit area and to the Mauna Kea and Mauna Loa volcanoes on the Big Island. Each volcanic mountain has its own unique type of silversword. The Haleakalā species is highly threated and is considered by many to be the most beautiful. But they are growing rarer due to drought, especially at lower elevations on the volcano slopes.

In a new study in the Ecological Society of America's journal Ecological Monographs, researchers seek to understand recent population declines of Haleakalā silverswords and identify conservation strategies for the future.

Because silverswords grow at high elevations between 5,000 and 10,000 feet, they have thoroughly adapted to the harsh environment there. These plants, with very dense rosettes of spiky leaves that radiate out from the base, produce towering blooms that can reach up to six feet high. The plants live from 15 to more than 50 years, but they bloom only once and die. Climate change imposes a new threat to these charismatic plants: hotter and drier conditions threaten even hardy silverswords.

Researchers with the University of Hawai'i are actively working with Haleakalā National Park staff to evaluate the effects of drought conditions on silverswords and to preserve these unique plants for generations to come.

Paul Krushelnycky, a researcher with the University of Hawai'i, and colleagues tracked growth of silversword plants for over three and a half years in greenhouse and out-planting experiments at the bottom, middle, and top of the plant's elevation range on Haleakalā. They studied the adaptability of silverswords to environmental or climatic changes and they also studied the plants' genes to see if some plants have genes that help them withstand drought better than others.

In the experiments, researchers found a counter-intuitive result, but one that is in line with what has been seen in the wild. "Plants have been dying at greater rates in wetter portions of the range, in response to drying conditions, rather than in drier areas," says Krushelnycky. "It's contrary to the prediction that one would normally make - namely, that the population should shift towards wetter areas as conditions get drier." 

It appears that lower elevation plants are less drought-resistant than higher elevation plants, which are already living in a drier environment and are thus more adaptable to extra-stressful dry seasons. The plants at lower elevation are thus dying off more than their higher counterparts during recent dry seasons. This pattern may be enhanced by strong changes in typical climate conditions at lower elevations.

One such change, and an extremely important factor for Hawai'i volcano climate overall, is the frequency and elevation of the trade wind inversion (TWI). "It's the trade wind inversion, not the trade winds per se, that is important in creating the relevant ecotone high on the mountain," explains Krushelnycky. "Above the TWI, it's much drier and clearer most of the time, and this appears to be important in determining not just the lower boundary of silverswords, but also the boundaries of several plant communities on the mountain."

An inversion is a layer in the atmosphere in which temperature increases, not decreases, with height, creating a kind of 'cap' of warm air. In Hawai'i this commonly occurs at about 6,000 to 8,000 feet. The presence of the TWI influences many aspects of Hawai'ian climate, including limiting cloud height, limiting the amount of rainfall on the islands, and producing dry air and clear skies at the highest elevations on volcanoes. Because the TWI limits how far air can rise, it plays a big part in how strong convective clouds and showers can become - a lower TWI elevation leads to lighter rainshowers or clouds with no showers at all.

The occurrence of the TWI has increased in recent decades, which leads to more persistent clear and dry - and thus stressful - conditions high on Haleakalā. Kryschelnycky says some climate projections predict TWIs will be even more frequent in the future, and possibly at lower elevation. Both of these changes would lead to more of the silversword range being exposed to stressful conditions. All in all, the changing climate would jeopardize the plants' survival even more. 

The delicate silverswords, once ripped up and taken home by visitors as souvenirs before the creation of Haleakalā National Park, now depend on management efforts for survival. Park staff fence out predators, destroy non-native plants that would crowd out silverswords, and educate park visitors to stay on trails to avoid stepping on fragile silversword seedlings and root systems. As for future management, Krushelnycky believes efforts should focus on using suitable places for silverswords to live in the face of climate changes, rather than trying to find or breed the silverswords with particularly drought-resistant genes.

"The study highlights how plant population responses to changing climate can be quite complex," says Krushelnycky, "both in terms of the underlying mechanisms and the outcomes." With continued study of silverswords and similarly-affected plants, the researchers think case studies like this will reveal more factors essential for consideration in broader conservation efforts.

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Ecological Society of America

Lung images of twins with asthma add to understanding of the disease

image: Researchers used a specialized MRI techniques to visualize the lungs of twins with asthma. While the twins are non-identical, the researchers found that they actually had identical ventilation defects in the same upper left lung segment, which stayed the same over the duration of the seven year study.

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Schulich Medicine & Dentistry

Two lung imaging studies from Western University, including one performed in non-identical twin patients with life-long asthma, have shown that airway defects in the lungs of asthmatic patients are like thumbprints - they have a unique pattern and maintain that pattern over time.

These studies deepen our understanding of asthma and also open up opportunities for personalized therapies that can target specific areas of the lungs.
In a study published recently in the journal Radiology, researchers used a specialized MRI technique developed at Western's Schulich School of Medicine & Dentistry, to follow 11 patients with mild to moderate asthma over a six year period and were able to visualize where air goes in the lungs and more importantly, where it does not.

These pockets of the lungs where there is no fresh air are called ventilation defects, and researchers and clinicians have long thought that these defects are random, wide-spread and change their location in the lungs depending on a number of factors in patients with asthma.

These studies refute that long-standing belief.

"Most of the patients in our study had essentially the same ventilation defects at the first visit and six years later both in terms of size and spatial location in the lungs," said Rachel Eddy, PhD

Candidate at Schulich Medicine & Dentistry and lead author on the studies. "This tells us that there are focal regions inside the lungs that are abnormal, and these stay that way over time."

In a case study published today in the journal Chest the researchers used the same technique in a set of twins with asthma. While the twins are non-identical, the researchers found that they actually had identical ventilation defects in the same upper left lung segment, which stayed the same over the duration of the seven year study.

"This result found in twins helps us further understand that asthma is not random, and asthma abnormalities persist over long periods of time in the same lung regions. The airway abnormalities likely have a heritable and environmental component," said Grace Parraga, PhD, Tier 1 Canada Research Chair, Professor at Schulich Medicine & Dentistry and Scientist at Robarts Research Institute.

This finding emphasizes the importance of personalized and image-guided therapy for asthmatic patients. "We see now that patients have different thumbprints of disease, and this points to the need for therapy that is patient-specific," said Dr. Cory Yamashita, Associate Professor of Respirology at Schulich Medicine & Dentistry.

The researchers also looked at how the MRI ventilation defects predict those patients that transition from asthma to chronic obstructive pulmonary disease (COPD), which does not respond to treatments that help open up closed airways. This novel finding supports previous health care database results and is critical because COPD patients experience constant and persistent shortness of breath and require more hospital-based care and much worse outcomes.

"COPD patients have difficult-to-treat disease - experiencing life-altering acute worsening more frequently and requiring more frequent hospitalizations," said Parraga. "If we can predict those that transition from asthma to COPD, perhaps we can find new ways to prevent this from happening in the first place. This would save countless health care dollars, decrease hospitalizations, and improve quality of life and disease control in patients."

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University of Western Ontario

A week in the dark rewires brain cell networks and changes hearing in adult mice

Scientists have known that depriving adult mice of vision can increase the sensitivity of individual neurons in the part of the brain devoted to hearing. New research from biologists at the University of Maryland revealed that sight deprivation also changes the way brain cells interact with one another, altering neuronal networks and shifting the mice's sensitivity to different frequencies. The research was published in the November 11, 2019 issue of the journal eNeuro.

"This study reinforces what we are learning about how manipulating vision can have a significant effect on the ability of an animal to hear long after the window for auditory learning was thought to have closed," said Patrick Kanold, professor of biology at UMD and senior author of the study.

It was once thought that the sensory regions of the brain were not adaptable after a critical period in childhood. This is why children learn languages much more readily than adults. Kanold's earlier research disproved this idea by showing that depriving adult mice of vision for a short period increased the sensitivity of individual neurons in the auditory cortex, which is devoted to hearing.

The current study expands on that earlier work. Kanold and his team investigated how exposure to darkness affects the way groups of neurons in the auditory cortex work together in response to a given sound--which neurons are connected and which fire more powerfully or faster. The researchers placed adult mice in a dark space for one week and then played 17 different tones while measuring brain activity in the auditory cortex. Based on their earlier work, Kanold and his team expected to see changes in the neural networks, but they were surprised to find that groups of neurons changed in different ways.

Young brains wire themselves according to the sounds they hear frequently, allocating areas of the auditory cortex for specific frequencies based on what they are used to hearing. The researchers found that, in adult mice, a week in the dark also redistributed the allocation of space to different frequencies. In the areas of the auditory cortex they examined, the researchers saw an increase in the proportion of neurons that were sensitive to high and low frequencies and a decrease in proportion of neurons that were sensitive to mid-range frequencies.

"We don't know why we are seeing these patterns," Kanold said. "We speculate that it may have to do with what the mice are paying attention to while they are in the dark. Maybe they pay attention to the noises or voices from the other mice, or maybe they're paying more attention to the footsteps they are making."

Kanold said his next steps include manipulating the sounds the mice are exposed to during the darkness phase of the experiment and monitoring brain activity to determine what aspects of their soundscape the mice are listening to. This will help the researchers understand the role of focus and attention in promoting change to the auditory neurons. Such information could be very useful in helping people adapt to cochlear implants or hearing aids.

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University of Maryland

Brain diseases with molecular diversity

Parkinson's and multisystem atrophy (MSA) - both of them neurodegenerative diseases - are associated with the accumulation of alpha-synuclein proteins in the brain. Researchers at the German Center for Neurodegenerative Diseases (DZNE) and the Max Planck Institute for Biophysical Chemistry (MPI-BPC) have investigated the molecular makeup of these protein deposits finding structural diversity. Experts from South Korea, Australia, and Argentina were also involved in the study. The results, published in the scientific journal "Nature Communications", suggest that Parkinson's might be related to diverse types of protein aggregates.

Alpha-synuclein is a protein that occurs naturally in the body. It is assumed to be involved in signal transmission between neurons. The protein appears both at the cell membrane and solved - floating, so to speak - in the cell's interior. In addition to these "normal" variants, there are others that manifest in brain diseases. This applies e. g. to Parkinson's disease and MSA. Both can be associated with various neurological impairments, including movement disorders. In Parkinson's and MSA alpha-synuclein molecules stick together. As a result, elongated aggregates arise that are deposited inside neurons and other brain cells. "These deposits successively appear in various areas of the brain. They are a disease hallmark," explains Prof. Markus Zweckstetter, who heads a research group at the DZNE and the MPI-BPC. "There is evidence that these aggregates are harmful to neurons and promote disease progression."

A Matter of Folding

These deposits represent a potential starting point for medicines. The idea is that drugs might prevent alpha-synuclein molecules from sticking together or dissolve existing aggregates. To identify potential docking sites for agents, data on the aggregates' fine structure is required. Thus, the question is: What kind of shape (also known as "folding") do the molecules adopt within the aggregates? So far, information on this topic had been limited to data from laboratory experiments. "Previous studies investigated the molecular structure of aggregates that were synthesized in a test tube. We asked ourselves how well such artificially produced specimens reflect the patient's situation. That is why we studied aggregates generated from tissue samples from patients," said Zweckstetter. "We collaborated closely with international partners on this project. In fact, the tissue samples originated in Australia and the aggregates were synthesized in South Korea. We then did the structural studies in Göttingen."

Aggregates from brain samples taken from five deceased Parkinson's patients and five deceased MSA patients were examined. For comparison, the researchers artificially produced different variants of alpha-synuclein aggregates. For this, they used standard procedures. To compare the structure of the different aggregates, they applied nuclear magnetic resonance spectroscopy and other methods.

Structural Differences

"We found that aggregated proteins that came from the lab were structurally different to all aggregates generated from patient material," Dr. Timo Strohäker, first author of the study, commented on the findings. "In addition, proteins of MSA patients differed from those of Parkinson's patients. If one looks at the data more closely, you notice that the proteins of the MSA patients all had a largely similar shape. The proteins of the patients with Parkinson's were more heterogeneous. When comparing the proteins of individual Parkinson's patients, there is a certain structural diversity."

The alpha-synuclein proteins of all aggregates contain "beta sheets", which is in line with previous investigations. Accordingly, the molecular backbone is twisted in a way that the proteins are largely two-dimensional. Within the aggregates, the proteins stick together in layers. However, folding does not encompass the whole protein. Each protein also contains areas that are unstructured. Besides, orientation of the beta sheets bears significance. "It is a question of how much of a protein is folded and also how it is folded," Zweckstetter stated.

Various Types of Aggregates in Parkinson's

In the structure of the alpha-synuclein associated with Parkinson's, there were some significant differences between patients. This might be due to the fact that the course of Parkinson's can vary quite considerably between individuals. "The variability of Parkinson's disease could be related to differences in the folding of aggregated alpha-synuclein. This would be in contrast to the 'one disease-one strain' hypothesis, that is to say that Parkinson's disease is associated with one, clearly defined aggregate form. However, in view of our relatively small sample of five patients, this is just a guess," said Zweckstetter. "Yet, our results certainly prove that studies with tissue samples from patients are necessary to complement lab experiments in a sensible way."

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DZNE - German Center for Neurodegenerative Diseases

Sun's close-up reveals atmosphere hopping with highly energetic particles

image: On its first two flybys of the sun, the Princeton-led instrument IS?IS onboard the Parker Solar Probe detected a surprising variety of activities by solar energetic particles -- the zippy electrons, protons and other ions that fly out in advance of the solar wind -- that can disrupt space travel and communications on Earth. The observations are just the beginning of explorations of how these particle events form, findings that will shed light on broader questions about the sun, space weather and cosmic rays. One of the greatest threats from the sun -- to astronauts and the satellites that provide GPS maps, cell phone service and internet access -- are high-energy particles that erupt from the sun in bursts. Top: On Nov. 17, 2018, the 321st day of that year, Parker Solar Probe's IS?IS observed a burst of high-energy protons, each with more than 1 million electron-volts of energy. The warmer colors (yellow, orange, red) represent an increase in the number of these high-energy particles hitting the IS?IS sensors. Bottom: An artist's representation of one of these energetic particle events.

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Image by Jamey Szalay and David McComas; Adapted with permission from D.J. McComas et al., Nature 575:7785 (2019)

Outbursts of energetic particles that hurtle out from the sun and can disrupt space communications may be even more varied and numerous than previously thought, according to results from the closest-ever flyby of the sun.

The new findings, which help us understand the sun's activity and ultimately could provide an early warning for solar storms, come from one of the four instrument suites aboard NASA's Parker Solar Probe, a spacecraft that has completed its first passes near the fiery orb. Results from all four suites appear today in a set of articles published in the journal Nature.

The finding that these energetic particle events are more varied and numerous than previously known was one of several discoveries made by the instrument suite known as the Integrated Science Investigation of the Sun (ISOIS), a project led by Princeton University that involves multiple institutions as well as NASA.

"This study marks a major milestone with humanity's reconnaissance of the near-sun environment," said David McComas, the principal investigator for the ISOIS instrument suite, a Princeton professor of astrophysical sciences and the vice president for the Princeton Plasma Physics Laboratory. "It provides the first direct observations of the energetic particle environment in the region just above the sun's upper atmosphere, the corona.

"Seeing these observations has been a continuous 'eureka moment,'" McComas said. "Whenever we receive new data from the spacecraft, we are witnessing something that no one has ever seen before. That is about as good as it gets!"

ISOIS seeks to find out how the particles become so fast moving, and what is pushing them to accelerate. The scientists searching for these answers includes ISOIS team members at the California Institute of Technology (Caltech), John Hopkins University Applied Physics Laboratory (APL), NASA Goddard Space Flight Center, NASA Jet Propulsion Laboratory, the University of New Hampshire, Southwest Research Institute, the University of Delaware and the University of Arizona, as well as collaborators at the University of California-Berkeley, Imperial College London, the University of Michigan, Smithsonian Astrophysical Observatory and the National Center for Scientific Research in France.

Highly energetic particles can disrupt communications and global positioning systems (GPS) satellites. These streams of particles, made up primarily of protons, have two sources. The first is from outside our solar system, generated when exploding stars release streams of particles known as cosmic rays. The other is our sun. Both can damage the electrical systems of spacecraft and are forms of radiation that can harm astronauts' health.

These energetic particles fly much faster than the solar wind, which is the roughly million mile-per-hour flow of hot electrically charged gas that whips off the sun. If the solar wind were a stream, the energetic particles would be fish that leap out and jump ahead of the flow. The particles travel along pathways -- called magnetic flux tubes -- that extend from the corona out into the solar wind.

Understanding these particles could improve space weather forecasts and give early warning of the massive storms that can disrupt Earthly communications and space travel.

"The answer to questions about how energetic particles form and accelerate is incredibly important," said Ralph McNutt, who oversaw the building of the lower energy of the suite's two instruments and is chief scientist in the Space Exploration Sector at APL. "These particles affect our activities on Earth and our ability to get our astronauts out into space. We are making history with this mission."

Due to their speed, the particles act as an early warning signal for space weather, said Jamey Szalay, an associate research scholar in the Department of Astrophysical Sciences at Princeton who leads the data visualization efforts for ISOIS. "These particles are moving fast, so if there is a big solar storm on its way, these particles are the first indicators."

Most previous studies of solar energetic particles relied on detectors located in space about the same distance from the Sun as is the Earth -- 93 million miles from the sun. By the time the particles get to those detectors, it is hard to track where they came from, because the particles from various sources have interacted and intermixed.

"It's a bit like cars coming from crowded tunnels and bridges and spreading out onto interstate highways," McComas said. "They get faster as they move away, but they also get mixed and interact in ways that it is impossible to tell who came from where as you move farther and farther away from the sources."

In its first trips around the sun, the Parker Solar Probe travelled twice as close to the sun as any previous spacecraft has ever been. At its closest, the spacecraft was 14 million miles -- or 35 solar radii, which is 17.5 widths of the sun -- from the fiery surface.

Getting close to the sun is essential for unraveling how these particles form and gain high energies, said Eric Christian, the deputy principal investigator on ISOIS and a senior research scientist at NASA Goddard. "It is like trying to measure what is happening in a mountain by studying the base of the mountain. To know what is happening, you have to go where the action is: You have to go up on the mountain."

A potential concern of the researchers was that the sun's 11-year cycle of activity is presently at a low. But the low activity level turned out to be an advantage.

"The fact that the sun was quiet allowed us to analyze events that are extremely isolated," said Nathan Schwadron, a professor of physics and astronomy and the head of the ISOIS science operation center at the University of New Hampshire. "These are events that haven't been seen from farther away because they are just clobbered by the solar wind activity."

During its first two orbits, ISOIS observed several fascinating phenomena. One was a burst of energetic particle activity that coincided with a coronal mass ejection, a violent eruption of energized and magnetized particles from the corona. Prior to the ejection, ISOIS detected a buildup of relatively low energetic particles, whereas after the ejection there was a buildup of high energetic particles. These events were small and not detectable from the Earth's orbit.

Another observation from ISOIS was particle activity indicating a sort of solar wind traffic jam, which happens when the solar wind suddenly slows down, causing fast-moving solar wind to pile up behind it and forming a compressed region of particles. This buildup, which astrophysicists call a co-rotating interaction region, occurred out beyond Earth's orbit and sent high energy particles back toward the sun where they were observed by ISOIS.

Researchers are eager to understand the mechanisms by which the sun accelerates particles to high speeds. ISOIS's detection of each particle's identity -- whether it is hydrogen, helium, carbon, oxygen, iron or another element -- will help researchers further explore this question.

"There are two kinds of acceleration mechanisms, one that occurs in solar flares when magnetic fields reconnect, and another that occurs when you get shocks and compressions of the solar wind, but the details of how they cause particle acceleration are not that well understood," said Mark Wiedenbeck, a principal scientist at NASA's Jet Propulsion Laboratory, who oversaw the development of the higher energy instrument in the ISOIS suite. "The composition of the particles is a key diagnostic to tell us the acceleration mechanism."

ISOIS made its third brush by the sun on Sept. 1, and will make its next on Jan. 29, 2020. As the mission continues, the satellite will make a total of 24 orbits, each time getting closer to the solar surface, until it is roughly five sun-widths from the star. The researchers hope that future flybys will reveal insights into the source of the energetic particles. Do they start as "seed particles" that go on to attain higher energies?

Jamie Sue Rankin, a postdoctoral researcher at Princeton working in the McComas group, began working on the higher energy ISOIS instrument as a graduate student at Caltech.

"It has been neat to see this whole process develop over the past decade," Rankin said. "It is like surfing a wave: We built these instruments, made sure they were working, made adjustments to make sure the calibrations were right -- and now comes the exciting part, answering the questions that we set out to address.

"With any spacecraft, when you go out into space, you think you know what to expect, but there are always wonderful surprises that complicate our lives in the best way," she said. "That is what keeps us doing what we do."

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Princeton University

How to boost sales of fair trade and sustainable goods

A researcher from Georgetown University published a new paper in the Journal of Marketing, which examines how consumers approach sustainable buying decision making with on-demand production, where they are given power early in the development cycle.

The study, forthcoming in the January issue of the Journal of Marketing, is titled "Who Receives Credit or Blame? The Effects of Made-to-Order Production on Responses to Unethical and Ethical Company Production Practices" and is authored by Neeru Paharia.

Want to sell fair trade and sustainable products? Use made-to-order production and see how consumers respond favorably when given choice and voice in the development of goods they want.

Imagine a consumer sees a nice pair of shoes she would like to own. This same consumer also recently read an article accusing the shoe brand of using poor labor practices. Although this consumer does not endorse the use of poor labor practices, she nevertheless buys the shoes feeling little guilt, thinking that the damage has already been done. Now instead, imagine that the same shoe brand uses on-demand production. In this case, the brand produces the shoes only after the consumer orders the item from a catalog. Rationally, in both cases the consumer is choosing whether to purchase a product made with poor labor practices. However, in the case of on-demand production, would this consumer still make the purchase?

Many companies have recently found success using various types of on-demand business models. For example, Nike offers consumers the ability to customize their shoes with Nike ID. Custom Ink allows customers to design their own T-shirts. And on-demand printing companies allow customers to order out-of-print and rare titles. More recently, Amazon.com announced "The Drop," clothing made on-demand and designed by prominent influencers. The dominant wisdom behind these made-to-order business models is that they can improve operational efficiency and/or consumer preference fit. However, giving consumers a role in production also has the consequence of giving them direct responsibility over whether a product will be produced. For example, in the case of on-demand books, a book will be produced only if a consumer orders it. In their pursuit of made-to-order business models, marketing managers may have overlooked the consequences of giving consumers control over this aspect of production.

In this research, we argue that giving consumers control of production can prompt them to weigh ethical production attributes (e.g., recycled materials, pollution, underpaid labor) more heavily than when they simply choose premade products from inventory already in stores. While it is most often the firm that decides the ethical parameters of production (e.g., labor, pollution), when products are made-to-order, it is the consumer who ultimately decides whether the product will be produced. Overall, we demonstrate that when consumers are given responsibility for whether a product is produced (e.g., made-to-order, on-demand production, customization, preorders), a stronger link between consumers and production leads to anticipated feelings of guilt or gratification depending on the ethicality of the production process, which then mediates purchase intentions. This link is weaker when consumers do not participate in production (i.e., choosing premade products from inventory). Although firms typically choose their operational strategy based on economies of scale, inventory management, and fit with consumer preferences in mind, this study is the first to demonstrate that the interaction of operational strategy and production ethicality can have emotional consequences that impact consumer behavior.

Recent industry and consumer behavior research suggests that made-to-order production is becoming an increasingly important product strategy for firms. For example, prominent companies across various categories, including Levi's, Mars, LensCrafters, Dell, Hallmark, Keds, Ford, Nike, and Kraft, have jumped on the customization bandwagon and the use of preorders is common even for large companies, such as Apple. At the same time, companies that focus on responsible supply chains (e.g., Everlane, Patagonia) and certification standards (e.g., Fairtrade International, B-Corp, Energy Star, Marine Stewardship Council) are gaining traction. Major investors are also putting pressure on companies to increase social accountability.

This research has clear and actionable forward-looking recommendations for managers, suggesting that marrying these two strategies could be particularly effective. When deciding whether to give consumers control over production, managers should consider how it might influence how consumers weigh ethical attributes. If a company invests in more ethical production, it should try to strengthen the link (use made-to-order production), cue customers to think about their broad level of responsibility, and/or reduce diffusion of responsibility. Conversely, if a company has more negative ethical production, it should try to diminish a causal link (use made-to-stock production).

Firms may also want to be more strategic on how they organize their supply chains across a portfolio of products. For example, Timbuk2 produces its off-the-shelf bags abroad (in Indonesia and Vietnam) and its customized bags in the United States (where the labor conditions are presumably more favorable). Although the company may have a variety of economic reasons for setting up operations in this way, they might also have learned that customers feel a stronger connection with production in one case versus the other. As such, managers should think carefully about how control over production and ethical attributes interact in order to identify opportunities and avoid risks.

Credit: 
American Marketing Association

Bone and muscle health can 'make or break' care as we age

image: Founded in 1942, the American Geriatrics Society (AGS) is a nationwide, not-for-profit society of geriatrics healthcare professionals that has -- for more than 75 years -- worked to improve the health, independence, and quality of life of older people. Its nearly 6,000 members include geriatricians, geriatric nurses, social workers, family practitioners, physician assistants, pharmacists, and internists. The Society provides leadership to healthcare professionals, policymakers, and the public by implementing and advocating for programs in patient care, research, professional and public education, and public policy. For more information, visit AmericanGeriatrics.org.

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(C) 2019, American Geriatrics Society

Experts at a prestigious medical conference hosted by the American Geriatrics Society (AGS) and funded by the National Institutes of Health's (NIH's) National Institute on Aging (NIA) hope their work--reported this week in the Journal of the American Geriatrics Society (JAGS)--can help yield hard evidence to address the range of "soft tissue" and bone disorders that contribute to falls, fractures, and muscle loss as we age.

"Falls, fractures, and muscle loss all have a major impact on our health as older adults, not only because they stop us from keeping active but also because that inactivity can have a ripple effect on all aspects of health and quality of life," said Cathleen Colón-Emeric, MD, MHSc, FACP, AGSF, who co-chaired the AGS-NIA conference this past March. "By looking at some of the key and interrelated health conditions that can contribute to falls, fractures, and muscle loss, we hope we can contribute to closing knowledge gaps as we develop better care."

The AGS-NIA "U13" conference (the term for a scientific conference funded by the NIH) brought together more than 80 national and international experts to discuss the present and future state of research on age-related aspects of osteoporosis (the medical term for bones becoming weak or brittle) and soft-tissue disorders (so named because they impact muscle, fat, and other "soft" tissue under the skin). The conference came at a pivotal time. As the prevalence of bone and soft-tissue disorders mounts--it is estimated, for example, that one in four older women and one in 20 older men already have osteoporosis--so too do alarming and interrelated consequences. Osteoporosis and declines in soft-tissue health are known to increase risk for falls, fractures, and frailty, which in turn limit health, safety, and independence as mobility begins to wane.

For older adults and caregivers, the challenge rests in preventing these conditions as often as possible. For health professionals, that means addressing an even broader set of questions about when and how these conditions arise, and what can be done to reduce risks as much as possible. Attendees at the AGS-NIA U13 conference hope the answer lies in a deeper look at fundamentals: What we know, what we don't, and what we can change when we jointly consider age, bone and muscle health, and the health conditions linking them.

Conference attendees noted, for example, that a key research priority must be identifying the "prime movers in biology," or the principal treatment targets that can address the root causes of bone and soft-tissue concerns. Refining our knowledge of how medications and other interventions like diet and exercise impact individual cell types--and even whole body systems--will be key to improving care for us all as we age.

At the same time, current perspectives on health care and health research also need to change. Developing medications to address bone and soft tissue changes that come with age can be uniquely challenging, for example, because age itself is not a disease or research endpoint recognized by the U.S. Food and Drug Administration (the federal agency that bears responsibility for approving any current or future pharmaceutical treatments).

But measures of muscle and bone function may prove helpful in this regard since they hold promise for contributing to the development of treatments to delay, prevent, or reverse a key contributor to age-related decline: Senescence, or the loss of our body cells' power to divide and grow as they did when we were younger. Concurrently, the conference attendees also asserted that health care needs to embrace a "life-course approach" to treating bone and soft tissue concerns, since body composition and muscle function change as we grow older.

"We know more today than we ever have about the impact of bone and soft-tissue disorders on quality of life and risks for declining health and even death," Bruce Troen, MD, AGSF, co-chair of the meeting, observed. "We now need to chart a course toward identifying risk factors, health disparities, and promising interventions to treat and prevent these concerns. We're confident our work at the conference resulted in a roadmap for progress."

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American Geriatrics Society

Researchers uncover early adherence step in intestinal transit of Shigella

Boston, MA - The bacterial pathogen Shigella, often spread through contaminated food or water, is a leading cause of mortality in both children and older adults in the developing world. Although scientists have been studying Shigella for decades, no effective vaccine has been developed, and the pathogen has acquired resistance to many antibiotics. The recent discovery of an early adherence step in the infection cycle by researchers at Massachusetts General Hospital (MGH) could provide a new therapeutic target or even a new method for vaccine development.

As it moves through the digestive system, Shigella traverses the small intestine and subsequently infects the large intestine, causing cramping, diarrhea and dehydration in the disease called shigellosis. "We wanted to determine how Shigella makes its first contact with epithelial cells in the early stages of disease development," says Dr. Christina Faherty, senior author on the study published in mSphere. "Because of certain gene sequence annotations, and the way that Shigella appeared following growth in standard laboratory media, it was believed that Shigella strains do not produce fimbriae or other adherence factors." Fimbriae are short hair-like fibers that bacterial cells use to adhere to individual epithelial cells to instigate infection.

The work of Faherty and the research team has uncovered evidence of fimbriae that aid adherence to epithelial cells, an important step in the start of a shigellosis infection. "We mimicked the conditions that Shigella would face in its journey through the small intestine by adding bile salts and glucose to laboratory media," says Faherty. "With this method, we discovered what had been hidden in plain sight before--the gene expression profiles that enabled Shigella to initiate this early step in infection by attaching to the epithelial tissue of the host."

Researchers at the Mucosal Immunology and Biology Research Center at MGH performed comprehensive microscopy and genetic analyses of Shigella to determine its subsequent steps after leaving the stomach. Their results demonstrate that "at least three structural genes facilitate S. flexneri (strain) 2457T adherence for epithelial cell contact and biofilm formation." In other words, their findings contradict the current hypothesis that critical components in the gene clusters are unable to produce fimbriae or other adherence factors.

In earlier research, Faherty and colleagues determined that exposure to bile salts resulted in the formation of biofilms, a protective coating of bacterial communities. Faherty hypothesizes that this coating enables the pathogen to survive the harsh conditions of the small intestine to successfully enter the colon. Since biofilm formation requires adherence factors, and since bacterial cells dispersed from the biofilm adhere better to epithelial cells, the next step by the group was to investigate adherence factor expression under these conditions. This next step was indeed controversial given the hypotheses that Shigella does not produce adherence structures; yet, the comprehensive analyses provided strong evidence to the contrary.

Co-author Rachael Chanin notes that the group's most recent study confirms their earlier analyses that the "in vivo-like" conditions facilitated biofilm formation and adherence to epithelial cells through fimbriae attachment. "One of the main challenges in studying Shigella is the lack of animal models that faithfully recapitulate human disease," says Chanin. "Although there have been elegant and thorough studies of what happens when the pathogen enters colonic epithelial cells, we did not understand what happens during transit through the digestive system or how the bacterium approaches or interacts with host cells prior to entry. Our work begins to address these questions and underlines the importance of in vivo-like culture methods. It also shows that these methods may influence our experimental results--whether intentionally or unintentionally."

After the promising results from their bile salts and glucose laboratory model, the researchers added another component to their adherence analysis--a human intestinal organoid. The "mini-gut," created from stem cells isolated from intestinal tissue, represents a model of the human intestinal epithelium. Working with a mini-gut of the ascending colon, the researchers discovered the Shigella adherence structures making initial contact with epithelial cells. "We think these adherence factors used in the intestinal organoid model replicate the contact made with the epithelial cells in the colon in the initial stages of shigellosis," says Faherty.

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Massachusetts General Hospital

Deep biomarkers of aging and longevity: From research to applications

image: Using age predictors within specified age groups to infer causality and identify therapeutic interventions.

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Correspondence to: Alex Zhavoronkov email: alex@insilico.com

The deep age predictors can help advance aging research by establishing causal relationships in nonlinear systems.

Deep aging clocks can be used for identification of novel therapeutic targets, evaluating the efficacy of various interventions, data quality control, data economics, prediction of health trajectories, mortality, and many other applications.

Dr. Alex Zhavoronkov from Insilico Medicine, Hong Kong Science and Technology Park, in Hong Kong, China & The Buck Institute for Research on Aging in Novato, California, USA as well as The Biogerontology Research Foundation in London, UK said "The recent hype cycle in artificial intelligence (AI) resulted in substantial investment in machine learning and increase in available talent in almost every industry and country."

Over many generations humans have evolved to develop from a single-cell embryo within a female organism, come out, grow with the help of other humans, reach reproductive age, reproduce, take care of the young, and gradually decline.

Considering the average age of the Olympic athlete, the age of optimal performance can be safely defined as 20-30.

Lifestyle and behavioral modifications may help slow down the decline and keep the organism in the best possible state for its chronological age, a term commonly referred to as healthy aging.

To understand the differences between the healthy aging and unhealthy aging, evaluate the effects of the many lifestyle choices and a variety of emerging longevity interventions, it is essential to be able to track the rate of aging and develop a comprehensive set of aging biomarkers.

The Zhavoronkov Research Team concluded that Developing comprehensive granular multi-modal aging clocks will help get a better understanding of the aging processes, establish causal relationships, and identify preventative and therapeutic interventions.

One of the many promising applications of the deep aging clocks built into the generative adversarial networks is generation of synthetic biological data with age as a generation condition.

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Impact Journals LLC

Hundreds of environmental health professionals in US report challenges, research needs

image: This is Baylor University Researcher Bryan W. Brooks, Ph.D., director of Baylor University's Environmental Health Science Program

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Baylor University

Hundreds of environmental health professionals across the nation report challenges and research needs in six areas -- drinking water quality, wastewater management, healthy homes, food safety, public health pests and emerging issues such as disaster risk reduction and new facility types for body art and cannabis-infused products -- in research from Baylor University and partners.

The article -- "Environmental Health Practice Challenges and Research Needs for U.S. Health Departments" -- is published in the journal Environmental Health Perspectives. It explores new findings and builds on the initiative Understanding Needs, Challenges, Opportunities, Vision, and Emerging Roles in Environmental Health (UNCOVER EH), launched by partners Baylor University, the National Environmental Health Association and the Centers for Disease Control and Prevention in 2017.
More than 1,700 environmental health professionals in health departments across the country provided input for the effort to assess and improve the EH profession and practice. While EH represents one of the largest segments of the public health workforce, 26 percent of EH professionals working in United States health departments are expected to retire in five years, while only 6 percent of public health students are pursuing environmental health concentrations, as highlighted in the report.

READ MORE: https://www.baylor.edu/mediacommunications/doc.php/346677.pdf for UNCOVER EH visual abstract on key findings.

Lead author Bryan W. Brooks, Ph.D., Distinguished Professor of Environmental Science and Biomedical Studies, director of Baylor University's Environmental Health Science Program and editor-in-chief of the journal Environmental Management, discusses the article's findings in this Q&A.

Q: Why is this article so significant?

DR. BROOKS: Environmental health professionals are one of backbones of public health, working tirelessly to protect local communities from historic and emerging health threats. However, the work they do and the challenges and opportunities facing this profession have not been seriously studied in the U.S. since the early 1960s. This groundbreaking initiative, UNCOVER EH, is beginning to understand one of the largest segments of the public health workforce. The current study provides a clarion call to advance the delivery of the essential environmental public health services and protect the health of our families, friends and neighbors.

Q: How were the six general challenge areas determined?

DR. BROOKS: We employed a horizon-scanning method in which we simply asked environmental health professionals working in health departments across the U.S. what challenges they will be facing over the next five to 10 years. After receiving responses from over 1,700 professionals, their responses were partitioned among common themes, which were examined at a workshop with facilitated focus groups. Environmental health professions then distilled this information to develop several priority problem statements for each of the topic areas.

Q: Can you give some specific examples of problem statements identified as concerns by environmental health professionals who participated in the web-based survey and in-person workshops?

DR. BROOKS: We identified 29 priority problem statements across the workshop themes. Some of these challenges are highlighted in areas with limited capacity, including peri-urban and rural regions across the country. Though environmental health professionals continue to diagnose, intervene and prevent historic public health threats, the efforts they engage are becoming more diverse as emerging threats present new health risks. Important opportunities exist for innovative interventions to ensure clean water, safe food and healthy homes while addressing diverse communicable and noncommunicable diseases that are affecting local communities

Q: Any recommendations for ways EH professionals can better respond to challenges?

DR. BROOKS: This manuscript presents several timely recommendations for professional and academic training, expanding partnerships, including through nontraditional efforts, and translational research. For example, environmental health professionals should be more closely integrated within research teams to maximize the benefits of research funding. We specifically recommend launching a strategic national research initiative to address environmental health practice challenges and needs.

Q: What can the public can do to support EH professionals as they seek to improve their practice?

DR. BROOKS: Most folks aren't aware of the work environmental health professionals engage until something bad happens, and reports of contaminated drinking water, food-borne illness outbreaks, vector-borne diseases, or natural or man-made disasters appear on the news. I highly recommend resources from your local health department and websites from the CDC's National Center for Environmental Health, the National Environmental Health Association and the American Public Health Association.

Q: The article notes that 26 percent of EH professionals working in United States health departments are expected to retire in five years, while only 6 percent of public health students are pursuing environmental heath concentrations. That seems disturbing, given the environmental challenges. What can be done to attract and retain EH professionals in the future?

DR. BROOKS: Simply stated, we are experiencing important national health care challenges in this critical area. We need to increase the number of undergraduates and graduate students specializing in environmental health science. Expanded training and requiring credentials such as the Registered Environmental Health Specialist (REHS) can improve preparedness of the current workforce. A national scale effort to enhance environmental health workforce preparedness appears warranted.

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Baylor University

WFIRM scientists push bioprinting capability forward

image: Integrated tissue-organ printer (ITOP) bioprints a trachea construct at WFIRM.

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WFIRM

WINSTON-SALEM, NC, -- Dec. 4, 2019 -- Wake Forest Institute for Regenerative Medicine (WFIRM) scientists are the first to report using bioprinting to print a tracheal tissue construct comprised of multiple different functional materials. They printed different designs of smooth muscle and cartilage regions in artificial tracheal substitutes showing similar mechanical properties to human tracheal tissue.

Previous attempts of tissue engineered tracheal constructs have presented many different limitations, mainly because they focused only on using regenerated cartilage tissue. The WFIRM tracheal constructs are novel in that they were bioprinted with separate cartilage and smooth muscle regions at the same time using a biodegradable polyester material and hydrogels containing human mesenchymal stem cells which can self renew and can become a variety of cell types. In this case, the stem cells differentiated into two different cell types -- chondrocytes and smooth muscles cells -- in different regions of the bioprinted tracheal constructs. The cartilage portion is stiff to provide mechanical support to avoid collapse while the smooth muscle is pliable and connects the ends of the cartilage rings, allowing sufficient flexibility for airway contraction.

"People have tried other materials, but the problem has been they were using just one material that is not strong enough to hold the airways open and does not provide the flexibility needed. Our bioprinting method provides a combination of flexibility and strength needed to mimic native tracheal tissue," said Sean Murphy, PhD, lead author and assistant professor of regenerative medicine at WFIRM.

The trachea is a hollow tube that is made of cartilage and smooth muscle tissue designed to allow a flexible airway that resists collapse. Tracheal stenosis is the abnormal narrowing and stiffening of the trachea, which can be caused due to prolonged intubation, inflammation and trauma or it can be a congenital abnormality. The primary treatments for the condition, which is rare but life threatening, are surgical interventions that have challenges and limitations.

For this study, published online in the journal Biofabrication, the research approach combines three tailored technologies: patient specific medical imaging, hydrogels designed to drive differentiation of stem cells, and polymeric scaffolding mimicking specific biomechanical properties.

Murphy said the approach was to incorporate softer hydrogels containing stem cells into the pores of the bioprinted tracheal structures. "We already knew we could differentiate these cells in 2D into smooth muscle or cartilage, but the question of whether we could do that in bioprinted 3D constructs remained," he said. "We added growth factors to help give them the extra push they needed."

"This early proof-of-concept study shows that we can streamline bioprinting capabilities and could someday provide the opportunity for regenerative medicine treatments for the replacement of damaged or diseased tracheal regions," said Anthony Atala, M.D., director of WFIRM and co-author of the paper. "Next steps in the research would be to evaluate long-term function to ensure appropriate tissue formation and strength retention."

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Atrium Health Wake Forest Baptist

Drug decreases gut leakiness associated with ulcerative colitis

image: Declan McCole (right) and his graduate student Anica Sayoc-Becerra are seen here examining a culture flask of intestinal epithelial cells prior to treating them with tofacitinib.

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I. Pittalwala, UC Riverside.

RIVERSIDE, Calif. -- A research team led by biomedical scientists at the University of California, Riverside, has found that a drug approved by the FDA to treat rheumatoid arthritis and ulcerative colitis can repair permeability defects in the gut's epithelium.

Affecting roughly 1 million Americans, ulcerative colitis is a chronic inflammatory bowel disease of the large intestine in which the lining of the colon becomes inflamed and leaky. Affecting more than 2 million Americans, rheumatoid arthritis is an autoimmune disease in which the body's immune system attacks the joints.

The study is the first to show the drug, tofacitinib, also called Xeljanz, has a direct effect on cells lining the gut by correcting defects that occur in inflammation. Until now, the effects of tofacitinib on intestinal epithelial cell functions were largely unknown.

Tofacitinib was approved by the FDA for ulcerative colitis in 2018. The drug improves a clinical readout called "mucosal healing" but this was thought to be through effects on immune cells. The UC Riverside-led study shows that tofacitinib improves epithelial barrier function, an essential function of epithelial cells and a requirement for mucosal healing.

"Our work increases our understanding of how this drug is useful for treating ulcerative colitis," said Declan McCole, a professor of biomedical sciences in the UCR School of Medicine, and the lead author of the study that appears in the journal Inflammatory Bowel Diseases. "We now better understand where in the gut the drug is working, and how."

McCole explained that increased intestinal permeability -- or leakiness -- is a feature of ulcerative colitis and plays a critical role in promoting inflammation. His team tested tofacitinib in human intestinal epithelial cell lines, as well as in organoids, or colonoids, that were derived from primary human colonic stem cells isolated from human subjects -- primarily patients undergoing elective colonoscopy for colon cancer screening -- and found tofacitinib repaired inflammation-induced permeability defects in both.

The epithelium is a thin layer that lines the alimentary canal. The gastrointestinal epithelium is comprised of cells that have gaps between them, making them selectively permeable and providing a barrier that keeps out pathogens, toxins, and antigens from entering the gut, while allowing the absorption of nutrients. In ulcerative colitis, this epithelial permeability becomes leaky, allowing bacterial products to cross into the gut and nutrients and water to leak out. This, in turn, triggers immune responses, resulting in fluid loss and diarrhea.

"We found tofacitinib fixes the leakiness in the intestinal barrier," McCole said. "Specifically, it fixes intestinal epithelial permeability defects caused by 'interferon-gamma,' an inflammatory cytokine involved in autoimmune diseases such as ulcerative colitis and rheumatoid arthritis."

"By targeting specific molecules, the drug inhibits a pathway that is activated by inflammation," said Anica Sayoc-Becerra, a graduate student in the Biomedical Sciences Graduate Program, a member of McCole's lab, and the first author of the research paper. "Our study shows tofacitinib is not just acting on immune cells, as was first thought, but can have a direct effect on the epithelial cells that are the key factor in maintaining gut barrier function."

A major focus of McCole's lab is PTPN2, a protein-coding gene associated with autoimmune diseases such as Crohn's disease, ulcerative colitis, and rheumatoid arthritis. Individuals with mutations in this gene that cause it to lose function have an increased risk of getting these diseases. McCole's research group was the first to identify PTPN2 normally helps to protect the barrier function of the epithelial cells that line the gut.

"A patient that has a PTPN2 loss-of-function mutation is predicted to have a leakier gut," McCole said. "Rather than trying to repair PTPN2, my lab was successful in inhibiting some of the consequences of the loss-of-function mutation in this gene."

Sayoc-Becerra explained PTPN2 deactivates the same signaling pathway as tofacitinib.

"We thought tofacitinib might be a very effective way of correcting the defects that occur from the loss-of-function mutations of PTPN2 without having to introduce new genes into a cell, animal, or patient," she said.

McCole and Sayoc-Becerra were joined in the study by UC Riverside's Moorthy Krishnan, Jossue Jimenez, Rebecca Hernandez, Kyle Gibson, and Reyna Preciado; as well as Shujun Fan and Grant Butt of the University of Otago in New Zealand. Sayoc-Becerra expects to graduate with her doctoral degree in December 2019. This is her first paper as first author.

Next, the researchers plan to identify specific patients who may derive the greatest benefit from the drug. This will allow more targeted treatment of patients likely to be good responders to tofacitinib in a "personalized medicine" approach to treating this disease.

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University of California - Riverside

Contamination by metals can increase metabolic stress in mussels

A study of six beaches in the coastal city of Guarujá in São Paulo state (Southeast Brazil) suggests that urbanization may be a source of stress not only for humans but also for mussels. Researchers affiliated with the Federal University of São Paulo (UNIFESP) in Santos, Brazil, and the University of New South Wales (UNSW) in Sydney, Australia, found a direct correlation among the degree of urbanization, contamination of the sea by metals and the possible metabolic stress caused by these contaminants in mussels that live on the beaches of interest. The study was funded by São Paulo Research Foundation - FAPESP and published in Marine Pollution Bulletin.

The group collected mussels of the species Mytilaster solisianus, which inhabits these six beaches in large clumps by clinging to wave-washed intertidal rocks. This species is not consumed by humans; however, like others that are consumed and hence are economically significant, this species filters the seawater around it to extract and absorb oxygen and edible particles. As a result, it is vulnerable to contamination.

Specimens were collected from Guaiúba, Astúrias, Morro do Maluf, Mar Casado, Sorocotuba and Iporanga beaches. Analysis of the specimens showed, as expected, that the filtration performed by the mussels increased when the water contained a high concentration of particles. In contrast to studies conducted by other groups, however, this group found that filtering also intensified when the water contained few edible particles and high levels of copper, nickel and zinc.

These three metals are chemically similar and cannot be differentiated in a shellfish contamination analysis. Copper is known to have detrimental effects on a range of organisms, which explains the researchers' interest in this three-metal group.

However, the mussels' behavior remained unaltered when they were exposed to particles of iron and manganese.

"They may have been under metabolic stress, seeking more food and making gas exchanges in an effort to recoup the energy lost by trying to eliminate pollutants," said Ronaldo Christofoletti, a professor at UNIFESP's Institute of Marine Sciences (IMar) and the last author of the article.

The study was part of the project "Strength of ecological interactions and environmental mediation in coastal ecosystems, supported by a regular research grant from FAPESP.

The first author of the article was Aline Sbizera Martinez, a postdoctoral researcher at IMar-UNIFESP with a scholarship from FAPESP.

To confirm this hypothesis of augmented metabolic stress, Martinez is now conducting new tests that include measures of excretion and respiration as well as filtration rates.

"More stress makes these animals filter, excrete and breathe more intensely," Martinez said. "By measuring these rates, we can calculate what we call scope for growth, basically an indicator of the amount of energy left over for the animal to grow. We plan to use these metrics to find out whether the copper, nickel and zinc group is actually having a physiological effect on the mussels."

In the published study, the researchers also measured the biomass of the macrofauna associated with mussel colonies - barnacles, algae, worms and so on that feed on the mussels' feces. Although mussels excrete more when they are exposed to metals, given that they must also filter and feed more intensely, contamination did not alter the biomass of the associated macrofauna. The researchers now plan to see if contamination affects the macrofauna's species diversity.

Differences

One of the differences between the currently published study and the research conducted previously by other groups resided in the experimental methods used to measure the mussels' filtration. Previous studies, which observed a reduction in filtration when the environment contained metal particles, were performed in the laboratory with animals collected from relatively clean areas and submitted to varying amounts of metal particles. In contrast, the UNIFESP group's experiments were conducted at the collection sites themselves.

"These studies conveyed the idea that filtration decreases when levels of pollutants increase, but when we performed our experiments in the field, in the environment where these animals live, filtration increased even when contamination levels were high," Christofoletti said.

In their experiments, the researchers placed approximately 100 cm² of mussels in a bucket with four liters of water from the collection site and measured the quantity of particles present in the water twice - once immediately after the mussels were placed in the bucket and again one hour later.

The difference between the two measurements was considered equivalent to the quantity of particles retained by the mussels.

"In our experiments, we analyzed animals that lived in the environment at the site and used the water they actually lived in," Christofoletti explained. "They had adapted to higher levels of particles of these metals. Collecting them from a pristine area and later adding the metals would be a major shock to their metabolism. You would expect them to stop filtering initially."

Urbanization

The copper-nickel-zinc group is abundant in the Santos Bay area because of the Port of Santos, the largest port in Latin America. These metals originate from the anti-fouling paint used to prevent barnacles and other aquatic organisms from attaching themselves to ships' hulls. They also come from shampoo, engine oil, and even atmospheric pollution that mixes with rain and is discharged onto the beaches by stormwater drains.

Santos Bay and the coastal plain south of the city (known as Baixada Santista) also contain one of Brazil's largest industrial clusters, as well as a large region characterized by urban sprawl, with nine densely populated municipalities and a total of 1.85 million inhabitants. Not by chance, the researchers found a direct correlation between the degree of urbanization and the levels of these metals in the mussels.

Using images from Google Earth, the researchers identified the urban districts from which stormwater runoff was discharged onto each of the six beaches analyzed. They then measured the urban cover using special software. The more urbanized the area was, the greater the contamination of the corresponding shoreline.

"There's a direct correlation between urbanization and contamination of organisms. This was expected, but we now have evidence for our coastal areas," Martinez said.

The researchers propose that this evidence should be used as input to public policy for the region with the aim of mitigating the impacts of human activities on coastal and marine ecosystems.

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Fundação de Amparo à Pesquisa do Estado de São Paulo