Culture

20 people die every day waiting for an organ transplant in the United States, and while more than 30,000 transplants are now performed annually, there are over 113,000 patients currently on organ waitlists. Artificially grown human organs are seen by many as the "holy grail" for resolving this organ shortage, and advances in 3D printing have led to a boom in using that technique to build living tissue constructs in the shape of human organs. However, all 3D-printed human tissues to date lack the cellular density and organ-level functions required for them to be used in organ repair and replacement.

Now, a new technique called SWIFT (sacrificial writing into functional tissue) created by researchers from Harvard's Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS), overcomes that major hurdle by 3D printing vascular channels into living matrices composed of stem-cell-derived organ building blocks (OBBs), yielding viable, organ-specific tissues with high cell density and function. The research is reported in Science Advances.

"This is an entirely new paradigm for tissue fabrication," said co-first author Mark Skylar-Scott, Ph.D., a Research Associate at the Wyss Institute. "Rather than trying to 3D-print an entire organ's worth of cells, SWIFT focuses on only printing the vessels necessary to support a living tissue construct that contains large quantities of OBBs, which may ultimately be used therapeutically to repair and replace human organs with lab-grown versions containing patients' own cells."

SWIFT involves a two-step process that begins with forming hundreds of thousands of stem-cell-derived aggregates into a dense, living matrix of OBBs that contains about 200 million cells per milliliter. Next, a vascular network through which oxygen and other nutrients can be delivered to the cells is embedded within the matrix by writing and removing a sacrificial ink. "Forming a dense matrix from these OBBs kills two birds with one stone: not only does it achieve a high cellular density akin to that of human organs, but the matrix's viscosity also enables printing of a pervasive network of perfusable channels within it to mimic the blood vessels that support human organs," said co-first author Sébastien Uzel, PhD., a Research Associate at the Wyss Institute and SEAS.

The cellular aggregates used in the SWIFT method are derived from adult induced pluripotent stem cells, which are mixed with a tailored extracellular matrix (ECM) solution to make a living matrix that is compacted via centrifugation. At cold temperatures (0-4 ?C), the dense matrix has the consistency of mayonnaise - soft enough to manipulate without damaging the cells, but thick enough to hold its shape - making it the perfect medium for sacrificial 3D printing. In this technique, a thin nozzle moves through this matrix depositing a strand of gelatin "ink" that pushes cells out of the way without damaging them.

When the cold matrix is heated to 37 ?C, it stiffens to become more solid (like an omelet being cooked) while the gelatin ink melts and can be washed out, leaving behind a network of channels embedded within the tissue construct that can be perfused with oxygenated media to nourish the cells. The researchers were able to vary the diameter of the channels from 400 micrometers to 1 millimeter, and seamlessly connected them to form branching vascular networks within the tissues.

Organ-specific tissues that were printed with embedded vascular channels using SWIFT and perfused in this manner remained viable, while tissues grown without these channels experienced cell death in their cores within 12 hours. To see whether the tissues displayed organ-specific functions, the team printed, evacuated, and perfused a branching channel architecture into a matrix consisting of heart-derived cells and flowed media through the channels for over a week. During that time, the cardiac OBBs fused together to form a more solid cardiac tissue whose contractions became more synchronous and over 20 times stronger, mimicking key features of a human heart.

"Our SWIFT biomanufacturing method is highly effective at creating organ-specific tissues at scale from OBBs ranging from aggregates of primary cells to stem-cell-derived organoids," said corresponding author Jennifer Lewis, Sc.D., who is a Core Faculty Member at the Wyss Institute as well as the Hansjörg Wyss Professor of Biologically Inspired Engineering at SEAS. "By integrating recent advances from stem-cell researchers with the bioprinting methods developed by my lab, we believe SWIFT will greatly advance the field of organ engineering around the world."

Collaborations are underway with Wyss Institute faculty members Chris Chen, M.D., Ph.D. at Boston University and Sangeeta Bhatia, M.D., Ph.D., at MIT to implant these tissues into animal models and explore their host integration, as part of the 3D Organ Engineering Initiative co-led by Lewis and Chris Chen.

"The ability to support living human tissues with vascular channels is a huge step toward the goal of creating functional human organs outside of the body," said Wyss Institute Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at HMS, the Vascular Biology Program at Boston Children's Hospital, and Professor of Bioengineering at SEAS. "We continue to be impressed by the achievements in Jennifer's lab including this research, which ultimately has the potential to dramatically improve both organ engineering and the lifespans of patients whose own organs are failing,"

Scientists have used MRI scanners to discover the parts of the brain which understand metaphors, in both healthy volunteers and people with schizophrenia. They found that people with schizophrenia employ different brain circuits to overcome initial lack of understanding. The researchers hope this identification of brain reactions and affected areas may help people with schizophrenia to better comprehend metaphors in everyday speech. This work is presented at the ECNP congress in Copenhagen.

People with schizophrenia have often problems in understanding some common figurative expressions, such as humour, irony, and spoken metaphors. They tend to take the metaphor at its literal meaning (for example, "a leap in the dark" may imply jumping and darkness for someone with schizophrenia): it may take some time for them to arrive at an understanding of what the metaphor is meant to imply. There has been little attempt to understand why this might be so at a neurological level.

A group of Polish and Czech researcher examined 30 patients who had been diagnosed with schizophrenia and 30 healthy controls. While undergoing a brain scan in a high-sensitivity MRI, they read 90 brief stories. 30 of the stories had a metaphorical ending, 30 had an absurd/nonsense ending, and 30 had a neutral ending (i.e. a literal ending). The scientists monitored brain activity while the subjects were reacting to the stories.

They found that compared to controls, the patient group showed increased brain activity in certain areas, but lower brain activity in others. For example, the healthy group showed brain activation in the prefrontal cortex (near the front of the brain) and left amygdala (at the centre of the brain, near the top of the brain stem), implying that these are the brain areas where metaphors are normally processed. Instead, schizophrenia patients showed a decreased activation in the temporal suculus (an area ascending from the low central brain towards the back of the head). Researcher Martin Jáni, from the Jagiellonian University, Krakow, Poland said:

"Previous researchers studied brain areas that are connected to impaired metaphor understanding in schizophrenia, so comparing metaphors with literal statements. However, by adding the absurd punchline, we were able to explore the stage at which the deficit occurs. We also used everyday metaphors, which would be easily understood.

We found that biggest changes in brain activity in schizophrenia patients occur during the basic stage of metaphor processing, that is when a person needs to recognize there is incongruity between the opening sentence and the punchline. These activated areas of the brain are very different to the brain areas activated in healthy patients, as if the brain is struggling to find a compensatory mechanism, to bypass the circuits normally used to understand metaphor".

It's likely that this inability to understand the sort of conventional metaphors we use in everyday life is socially isolating for people with schizophrenia. While this at the research stage, our hope is that we can develop practical skills in patients with schizophrenia - and indeed the people who know them - which will help them understand the speech the way it was intended"

Commenting, Dr Emilio Fernandez-Egea, University of Cambridge said;

"Understanding the neural basis of social cognition are of great relevance for people with schizophrenia. These deficits are often overlooked, despite the impact on the general functioning and in the ability to find and maintain social relationship and work. Expanding our knowledge of this often neglected domain will improve the recovery process in this population".

This is an independent comment; Dr Fernandez-Egea was not involved in this work.

EXAMPLES:

The metaphors themselves were commonly used in everyday Polish speech. They were incorporated in brief stories, such as:

Metaphor

On the street, man on the bike accidentally hits a pedestrian "I am sorry, are you alright?" asked the cyclist, to which the pedestrian replied "No, I am sorry, I shouldn't walk with my head in the clouds".

Comment: People with schizophrenia had more difficulty in pulling the metaphorical meaning away from the literal "head in the clouds" meaning.

Neutral

A man comes back home after unusually long day at work. His partner asks "Why are you so late? The dinner is already cold" He replies "I am very sorry. I had to finish an important project".

Comment: This is literal - there's no hidden meaning here.

Absurd (nonsensical)

Two colleagues are talking at work. One says "I can't believe that John is earning money than me for the same position!" The other says "The copy machine broke yesterday".

Comment: In this case the reply is not relevant to the question.

BIRMINGHAM, Ala. - Two rare but potentially deadly blood-clotting diseases, namely thrombotic thrombocytopenic purpura, or TTP, and hemolytic uremic syndrome, or HUS, show similar pathologies -- a multitude of painful blockages in small blood vessels that cause varying degrees of organ injury throughout the body. However, the two disorders have distinctbiological mechanisms.

Now, in a preclinical study published in the journal Blood, researchers have found a synergistic connection, or crosstalk, between the two disorders. Such a linkage between the two thrombotic microangiopathic disorders "may provide a rationale for a more targeted therapeutic intervention in patients with refractory thrombotic microangiopathy," said X. Long Zheng, M.D., Ph.D., who led a team of researchers at the University of Alabama at Birmingham.

At UAB, Zheng is the Robert B. Adams Professor of Pathology and Division Director of Laboratory Medicine in the Department of Pathology, UAB School of Medicine.

TTP is mostly caused by autoimmune antibodies that attack one of the body's own enzymes, ADAMTS13, first identified and cloned by Zheng in 2001. HUS, particularly the atypical form, is caused mostly by improper activation of complement through the alternative complement pathway, a part of the immune system that helps, or "complements," the clearance of infecting microbes or damaged cells from the body.

Some clinical evidence from patients with TTP led Zheng and colleagues at UAB and the University of Pennsylvania to test the hypothesis that there may be a synergy between ADAMTS13 deficiency and complement activation in pathogenesis of thrombotic microangiopathy.

They used two existing mouse lines -- one that completely lacks ADAMTS13 and one that has a heterozygous mutation in complement factor H gene, or cfh, where the mouse has one gene with unmutated cfh and one with the mutated cfh. Mammals like humans and mice have two copies of each chromosome, so there are two copies of the gene cfh.

These two lines are known as Adamts13-/-, which completely lacks the enzyme ADAMTS13, and cfhW/R, where the W indicates the amino acid tryptophan in the normal CFH protein from the unmutated gene, and R indicates that the tryptophan has been replaced by an arginine in the mutant CFH protein. Those two mouse lines remain completely asymptomatic for thrombotic microangiopathy despite the presence of occasional microvascular thrombi in various organ tissues on histology analysis.

To look for interactions between the pathogenic pathways for TTP and atypical HUS, the researchers generated a third strain, which showed the signs and symptoms, and laboratory evidence, of thrombotic microangiopathy.

They found that mice carrying both Adamts13-/- and cfhW/R showed thrombocytopenia, which is low counts of blood platelets because the platelets have left circulating blood to form blood clots. The mice also had low plasma haptoglobin and increased fragmentation of erythrocytes in peripheral blood smears, the signs of red blood cells that were broken trying to squeeze past blood clots. The mice also had increased plasma levels of lactate dehydrogenase activity, blood urea nitrogen and creatinine, signs of general organ damage and kidney damage from clots, and these mice also had an increased mortality rate.

Strains of mice that had the cfh mutation in both genes, known as the homozygous mutation cfhR/R, with or without Adamts13-/-, developed an even more severe thrombotic microangiopathy. The mortality rate in mice with both Adamts13-/-and cfhR/R was significantly higher than that in mice with cfhR/R alone.

All three affected mouse strains had microscopically visible disseminated platelet-rich thrombi in terminal arterioles and capillaries of major organ tissues, including brain, heart, lungs, kidney, liver and intestine.

"Altogether," Zheng said, "our results support the synergistic effects of ADAMTS13 deficiency and complement activation in the pathogenesis of thrombotic microangiopathy. The results may help design a potentially novel strategy to treat the refractory thrombotic microangiopathy in the future."

HOUSTON -- (Sept. 6, 2019) -- While collecting data from live oak trees in the world's largest medical center, Rice University evolutionary ecologists have discovered huge quantities of one of North America's most venomous caterpillars.

Live oak trees lining sidewalks in the Texas Medical Center (TMC) -- which is visited by 10 million people seeking health care each year -- are routinely netted to discourage pesky birds such as grackles and pigeons. Now Rice researchers have learned the netting has an unintended consequence: Chasing away birds that eat insects has created a haven for a flourishing population of Megalopyge opercularis, commonly referred to as asps.

The asps bristle with venomous spines that can cause severe pain for humans unlucky enough to come in contact with them. When a human is stung by an asp, it can cause localized pain that is compared to blunt-force trauma or a bone break. Symptoms include headaches, nausea, vomiting, fever, low blood pressure, inflammation of lymph nodes and, in severe cases, abdominal distress, muscle spasms, convulsions and respiratory stress.

"I've been stung by a lot of things and an asp sting definitely ranks high up there," said Mattheau Comerford, an ecology and evolutionary biology graduate student at Rice who is also a U.S. Army veteran. "It takes about 10 minutes before the pain kicks in so you might not even realize you've been stung at first. It feels like a broken bone and the pain lasts for hours. I was stung on the wrist and the pain traveled up my arm, into my arm pit, and my jaw started to feel pain."

The TMC, in addition to hosting a vulnerable population seeking health care, is the eighth-largest business district in the country, employing more than 106,000 people.

"There are a lot of people that congregate in the green spaces of TMC," said Glen Hood, a research assistant professor of biological sciences at Wayne State University and a former member of the Rice Academy of Fellows. "It becomes this scenario of what's worse -- bird guano or venomous asps -- and is there a happy medium?"

Scott Egan, an assistant professor of biosciences at Rice, has spent almost 20 years studying live oaks from Florida to Texas and is used to seeing the asps, which resemble tufts of fur. He said asp stings are common in live-oak country, even though the insects typically occur in low numbers under natural conditions.

"When we saw such high numbers of asps in the TMC, we knew this was something we needed to look into," he said. "The Egan Lab addresses important conceptual issues in ecology, evolution and conservation biology, and we do that through the lens of specializing in one single system."

As specialists in the live oak system, Egan and his team can observe unique differences or slight changes that a general scientist might not be able to see. That's what sparked the study entitled "Human-mediated disturbance in multitrophic interactions results in outbreak levels of North America's most venomous caterpillar," which is published in the journal Biology Letters.

"We thought this was a wonderful, natural, already-occurring experiment that we could exploit to understand what happens when trophic interactions get disrupted," Egan said. "We observed that there were a higher number of asps in the TMC than on Rice's campus, so we performed an observational study across many sites in this area over a three-year span: trees that have massive nets and deter birds, versus naturally occurring systems such as live oak trees and the caterpillars that feed on them."

Egan's team discovered that caterpillar abundance, on average, was more than 7,300% higher on netted versus non-netted trees.

"The patterns in the data are overwhelming and striking," said Hood, the study's lead author and a former postdoctoral research fellow in Egan's lab. "It's highly suggestive that when you don't take into account the natural interactions taking place within a community or ecosystem, even in an urban setting, it can cause unforeseen consequences."

Egan and his team was especially interested in the location of the netted trees -- lining the sidewalks, green spaces and streets of the TMC.

"In this area, there is a high density of people with allergies and compromised or depleted immune systems, putting them at a higher risk for the ill effects of the asp stings," Comerford said.

Egan said nuisance birds are a widespread problem, and the kind of nets used in the TMC are a common sight in cities, fruit orchards and commercial nurseries. He said TMC staff helped his team with its research, giving students access to trees and opening up netting for sample collection.

"There is no 'bad guy' here," Egan said. "Urban bird pests are a real problem, and birds can carry diseases and pose health risks, too. Netting trees is a way to address that problem, and we do not know if netting trees leads to an increase in asp stings. What our study shows is the complexity of the problem. Asps are yet another dimension to something that was already a multi-dimensional problem."

Humans may not be the only species at risk from asps. The Houston Zoo, located on the northeast edge of the TMC, houses more than 6,000 animals from 900 different species. Many zoos use netting to cover animal enclosures and observation areas, and Egan's team said that could facilitate similar asp outbreaks and increase animal and human exposure.

Amanda Weaver noticed the surge of asps covering netted trees in the TMC while she was working on a separate project for her senior thesis as an undergrad in the Egan Lab.

"I thought this project was really interesting because I had never heard of asps before I got to Rice," said Weaver, now a graduate student at Columbia University. "I remember getting the warning emails from Rice and seeing the rashes from my classmates who had been stung. Especially because they are not prevalent everywhere, my biggest concern is that people may not know they are venomous. In fact, they actually look cute."

Rice's status as a registered arboretum and its next-door proximity to the TMC allowed Egan's team to gather data from many sites over a three-year span.

"Like a lot of things in biology, this experiment happened serendipitously," Hood said. "If you're inquisitive and paying attention to the details, you'll see an opportunity to collect data."

By spotlighting an unforeseen consequence of ecological disturbance, Egan and his team hope the study emphasizes the importance of considering ecology in urban planning.

"When we try to manage environments, it's very difficult for us to predict all of the implications or consequences," Comerford said. "It's very easy to say the birds are a problem and we can fix it by removing their nesting sites. But if you don't think through the pipeline, you can ultimately create unintended downstream effects."

BIRMINGHAM, Ala. - Beta cells in the pancreas produce insulin. Their death is a key feature of Type 1 diabetes, and that loss starts long before diagnosis. However, there has been no straightforward way to measure that early loss.

Anath Shalev, M.D., and colleagues at the University of Alabama at Birmingham now have identified an early biomarker of Type 1 diabetes-associated beta-cell loss in humans -- microRNA-204, or miR-204.

"Serum miR-204," Shalev said, "may provide a much needed novel approach to assess early Type 1 diabetes-associated human beta-cell loss, even before onset of overt disease."

MicroRNAs are found in animal and plant cells, where they help control gene expression. In previous work, Shalev found that miR-204 plays key roles in regulating insulin production and other critical beta-cell processes.

Now, in a study published in the American Journal of Physiology-Endocrinology and Metabolism, Shalev and colleagues report that miR-204, which is highly enriched in human beta cells, is released by dying beta cells. After that release, it becomes detectable in circulating blood.

Measurements using human blood samples showed that serum miR-204 was elevated in children and adults with early Type 1 diabetes, and in people with autoantibodies who are at risk for Type 1 diabetes, but it was not elevated in Type 2 diabetes or another autoimmune disease. Furthermore, serum miR-204 levels were inversely correlated with remaining beta-cell function in recent-onset Type 1 diabetes.

"Having a non-invasive, straightforward method sensitive enough to detect early beta-cell loss -- especially prior to the diagnosis of Type 1 diabetes -- is critical in order to allow for any therapeutic intervention to be started as early as possible in the disease process and ideally before the majority of beta cells has been destroyed," Shalev said.

Shalev is a professor in the UAB Department of Medicine's Division of Endocrinology, Diabetes and Metabolism, and she directs the UAB Comprehensive Diabetes Center.

Study details

Discovery of the biomarker was a step-by-step, hypothesis-driven process, starting from the observation that miR-204 had 108-fold higher expression in pancreatic islet beta cells as compared to pancreatic alpha cells.

The researchers first showed that miR-204 was released by cultured rat beta cells after induction of cell death by streptozotocin. Then they showed that killing of beta cells in mice given streptozotocin led both to diabetes, as expected, and to a massive increase in serum miR-204 levels.

Next, they showed that Type 1 diabetes-associated inflammatory cytokines, which induce beta cell death, caused release of miR-204 from both cultured rat beta cells and primary human pancreatic islets.

To test miR-204 in humans, they looked at serum from people receiving autologous pancreatic islet transplantations. It is known that islet transplantation is associated with massive beta-cell death shortly after the transplantation. The researchers found that miR-204 levels in serum rose sharply, 20 to 40 minutes after islet infusion.

The researchers next found that serum miR-204 was significantly elevated in children with recent-onset Type 1 diabetes. It was also elevated nearly threefold in adults with recent onset Type 1 diabetes and more than twofold in people with autoantibodies that put them at risk for Type 1 diabetes.

In contrast, it was not significantly elevated in people with Type 2 diabetes or people with the autoimmune disease rheumatoid arthritis. It was not significantly elevated in people who have had Type 1 diabetes for a long time and have lost most of their beta cells.

Serum miR-204, Shalev and colleagues found, correlated with remaining beta-cell function, as measured by the "gold standard" of mixed-meal stimulated C-peptide area under the curve. Serum miR-204 also showed good predictive diagnostic power in the context of early Type 1 diabetes, including the ability to differentiate adult recent-onset Type 1 diabetes from Type 2 diabetes. That is useful because adults with Type 1 diabetes are often misdiagnosed when first found to have diabetes.

Artificial intelligence has become much more prominent in business processes recently, and was voted the number one trend in SIOP's Top 10 Workplace Trends for 2019. SIOP is currently celebrating Smarter Workplace Awareness Month to highlight trends like AI in an effort to help organizations grow and thrive in ways that may not be possible without the help of I-O psychology.

As AI continues to gain traction, it will be critical for organizations to include I-O psychologists on their data science teams to leverage expertise in psychological theory and methods in ensuring optimal outcomes for organizations.

"Artificial Intelligence in Talent Assessment and Selection" is the latest in the Society for Industrial and Organizational Psychology (SIOP) white paper series. Written by Neil Morelli, PhD, VP of Product and Assessment Science at Berke, this paper provides an overview of artificial intelligence in the workplace, provides practical to-dos for organizations considering AI tools for their hiring process, and explains how I-O psychologists can help along the way.

Media channels often feature stories on the "future of work," "the skills gap," "income inequality," and "globalization." What these stories have in common is a focus on the work people will do in the future and how they will be placed in those jobs. In other words, how people are hired and managed are interests among everyday people. AI is a driving force behind the workforce changes occurring and is a tool that can help hire people into jobs.

However, HR is late to the AI game. Anyone interested in the future of work, HR, or hiring should read this whitepaper to get up to speed on this evolving topic. Artificial intelligence is changing the way businesses operate and has the potential to revolutionize the way we select and retain talent. For businesses to take advantage of new technology, they must first understand it. AI is complex topic, but Morelli breaks it down in a relatable manner so that HR practitioners can take action.

In addition to providing an overview and background on the topic, Morelli discusses three next steps for consumers to consider before using an AI hiring tool. He explains the options of getting I-O psychologists involved, pairing AI-based tools with human decision makers, and applying a healthy amount of skepticism to marketing materials provided by vendors.

Read the new SIOP white paper here: http://ow.ly/K3LV50vY8yb

As fires throughout the nation have demonstrated over the last few weeks, fire season isn't ending any time soon.

While it's impossible to predict just where the next wildfire will start, new Department of Defense-sponsored research from Brigham Young University's Fire Research Lab is getting into the microscopic details of how fires initiate to provide more insight into how wildfires burn through wildland fuels.

"We are working on a small scale and hopefully that gives us some insight into what happens on a large scale," said fire expert Thomas H. Fletcher, BYU professor of chemical engineering. "We're trying to take some of the unpredictability out of fire by doing experiments in well-controlled environments."

For their experiments, Fletcher and co-authors loaded leaves of 14 shrub species (including the likes of Inkberry, Wax Myrtle, Fetterbush, Dwarf Palmetto and Sparkleberry) into the crucible of a thermogravimetric analyzer and slowly turned the heat up to 800 degrees Celsius. As they watched the leaves burn, they categorized the speed at which the plant broke down and the chemicals produced by the heat. They also compared the impact of two heat sources: convective (think of wind-driven fires) and radiative (from burning plant particles or flames).

The research found that the chemistry of shrubs makes a big difference in how fast they break down before they combust. That's important to know because the type of plant found on a mountain hillside may help predict how a fire will burn and how quickly it might jump to another plant species.

"Very detailed models that already exist take up to two weeks to run on very big computers and by that time, the fire has moved and it's not in the same place anymore," Fletcher said. "We're aiming towards giving answers on how a fire might propagate in the next 20 minutes or half hour instead of the next two weeks."

The studies are aimed at improving predictive models for both prescribed burns and for unplanned wildfires. With wildfires costing the Forest Service and state agencies billions of dollars to control annually, any research that can help make fire management more efficient is a high priority.

Case in point: The Pole Creek Fire that burned 102,000 acres in south Utah County last year started with a lightning strike that was left to burn out naturally. Unfortunately, hot, dry winds pushed it into a major threat to Spanish Fork, Elk Ridge and Mapleton. The fire, which later merged with another wildfire -- the Bald Mountain Fire -- ended up costing more than $6 million to contain.

"With all we've done to research them, fires are still out of control," Fletcher said. "Our model can't prevent a fire, but it can help with decisions on how to do manage fires so that when a fire starts, it doesn't blow up into a huge, uncontrollable fire."

LA JOLLA--(September 6, 2019) Plants can do many amazing things. Among their talents, they can manufacture compounds that help them repel pests, attract pollinators, cure infections and protect themselves from excess temperatures, drought and other hazards in the environment.

Researchers from the Salk Institute studying how plants evolved the abilities to make these natural chemicals have uncovered how an enzyme called chalcone isomerase evolved to enable plants to make products vital to their own survival. The researchers' hope is that this knowledge will inform the manufacture of products that are beneficial to humans, including medications and improved crops. The study appeared in the print version of ACS Catalysis on September 6, 2019.

"Since land plants first appeared on earth approximately 450 million years ago, they have developed a sophisticated metabolic system to transform carbon dioxide from the atmosphere into a myriad of natural chemicals in their roots, shoots and seeds," says Salk Professor Joseph Noel, the paper's senior author. "This is the culmination of work we've been doing in my lab for the past 20 years, trying to understand plant chemical evolution. It gives us detailed knowledge about how plants have developed this unique ability to make some very unusual but important molecules."

Previous research in the Noel lab looked at how these enzymes evolved from non-enzyme proteins, including studying more primitive versions of them that appear in organisms such as bacteria and fungi.

As an enzyme, chalcone isomerase acts as a catalyst to accelerate chemical reactions in plants. It also helps to ensure the chemicals that are made in the plant are the proper form, since molecules with the same chemical formula can take two different variations that are mirror images of each other (called isomers).

"In the pharmaceutical industry, it's important that the drugs being made are the correct version, or isomer, because using the wrong one can lead to unintended side effects," says Noel, who is director of Salk's Jack H. Skirball Center for Chemical Biology and Proteomics and holds the Arthur and Julie Woodrow Chair. "By studying how chalcone isomerase works, we can learn more about how to accelerate the manufacture of the correct isomers of pharmaceuticals and other products that may be important to human health."

In the current study, the investigators used several structural biology techniques to investigate the enzyme's unique shape and how its shape changes as it interacts with other molecules. They pinpointed the part of chalcone isomerase's structure that allowed it to catalyze reactions incredibly fast while also ensuring it makes the proper, biologically active isomer. These reactions lead to a host of activities in plants, including converting primary metabolites like phenylalanine and tyrosine into vital specialized molecules called flavonoids.

It turned out that one particular amino acid, arginine, that was one of many amino acids linked together in chalcone isomerase sat in a location, shaped by evolution, that allowed it to play the key role in how chalcone isomerase reactions were catalyzed.

"By doing structural studies and computer modeling, we could see the very precise positions of arginine within the enzyme's active site as the reaction proceeded," says first author Jason Burke, a former postdoctoral research in Noel's lab who is now an assistant professor at California State University San Bernardino. "Without that arginine, it doesn't work the same way."

Burke adds that this type of catalyst has been long sought by organic chemists. "This is an example of nature already solving a problem that chemists have been looking at for a long time," he adds.

"By understanding chalcone isomerase, we can create a new toolset that chemists will be able to use for the reactions they're studying," Noel says. "It's absolutely vital to have this kind of foundational knowledge to be able to design molecular systems that can carry out a particular task even in the next generation of nutritionally dense crops capable of transforming the greenhouse gas carbon dioxide into molecules essential for life."

For tens of millions of people, migration is a tough reality. What causes people to migrate away from their home countries, and what happens when they do? Migrants and their labor are responsible for moving hundreds of billions of dollars around the world annually. At their destinations, they affect populations, cultures, and economies. But their movement also has a major impact on the places they leave, including on how people use land.

"To effectively manage migration, you have to understand the linked effects of people moving from one place to another," says USU geographer and migration researcher Claudia Radel.

"Migrants we see today, including from Central America, often come from rural communities where people depend on small-scale farming--which is becoming more difficult," said Radel. "Sometimes people cut ties to the land when they leave--but our research shows that they also leave to afford to rent land or to buy seeds so they can keep farming, or to support family who keep using the land." Later many return home with new ideas, resources, and expectations for the places they left behind. This can have impacts in unanticipated ways, for example changing prices, as Radel reported with her co-authors in the journal Land.

"People who live on the economic edge don't have access to sufficient land resources, especially in rural Central America," said Radel, Associate Dean of the Quinney College of Natural Resources at Utah State University and recipient of a National Science Foundation CAREER research grant. This inequality makes those who are land-poor more vulnerable to the negative effects of climate change and food insecurity, sometimes pushing them out to neighboring countries--including the U.S.--to find paying work. Radel studies the effects of migration on the communities and environments that migrants leave behind. With NSF support she has expanded that research to study the environmental and land-system drivers of migration. Much of her research has been in southern Mexico, but for the last six years she has been working with a research team in Nicaragua and Guatemala.

Around the world, researchers like Radel are working to better understand the links between land systems and the migration of people. In a recent publication in Current Opinion in Environmental Sustainability, Radel and a group of international scholars assessed knowledge gaps. Some drivers of migration, like deforestation and land degradation, are fairly well understood. But there is a complex relationship between migration and the environmental conditions of land and its uses. Markets, politics and social safety nets, for example, shape the way changes in land drive migration, and vice versa.

More research is needed to understand how environmental changes lead to migration, said Radel, and to understand how migrants impact landscapes both at their destinations and at their origins--but themes are emerging. Globalization of agriculture, persisting socioeconomic inequalities, concentration of land ownership, climate change and closing frontiers are all key trends.

"One thing is certain," said Radel. "To understand and manage human migration, we need to understand how migration is linked to land and to the environment."

Scientists have developed a compound that successfully promotes rebuilding of the protective sheath around nerve cells that is damaged in conditions such as multiple sclerosis.

In a study published today in the journal Glia, scientists described successfully testing the compound in mice. Researchers at Oregon Health & Science University have already started to apply the compound on a rare population of macaque monkeys at the Oregon National Primate Research Center at OHSU who develop a disease that is similar to MS in humans.

"I think we'll know in about a year if this is the exact right drug to try in human clinical trials," said senior author Larry Sherman, Ph.D., an OHSU professor in the Division of Neuroscience at the primate center. "If it's not, we know from the mouse studies that this approach can work. The question is, can this drug be adapted to bigger human brains?"

The discovery culminates more than a decade of research following a 2005 breakthrough by Sherman's lab.

In that study, scientists discovered that a molecule called hyaluronic acid, or HA, accumulates in the brains of patients with MS. Further, the scientists linked this accumulation of HA to the failure of cells called oligodendrocytes to mature. Oligodendrocytes generate myelin.

Myelin, in turn, forms a protective sheath covering each nerve cell's axon - the threadlike portion of a cell that transmits electrical signals between cells.

Damage to myelin is associated with MS, stroke, brain injuries, and certain forms of dementia such as Alzheimer's disease. In addition, delay in myelination can affect infants born prematurely, leading to brain damage or cerebral palsy.

Subsequent studies led by the Sherman lab showed that HA is broken down into small fragments in multiple sclerosis lesions by enzymes called hyaluronidases. In collaboration with Stephen Back, M.D., Ph.D., a professor of pediatrics in the OHSU School of Medicine, Sherman discovered that the fragments of HA generated by hyaluronidases send a signal to immature oligodendrocytes not to turn on their myelin genes.

That led researchers to explore how they might block hyaluronidase activity and promote remyelination.

For the past decade, an international team of researchers led by OHSU has been working to develop a compound that neutralizes the hyaluronidase in the brains of patients with MS and other neurodegenerative diseases, thereby reviving the ability of progenitor cells to mature into myelin-producing oligodendrocytes.

The study published today describes a modified flavonoid - a class of chemicals found in fruits and vegetables - that does just that.

The compound, called S3, reverses the effect of HA in constraining the growth of oligodendrocytes and promotes functional remyelination in mice. Lead author Weiping Su, Ph.D., senior scientist in the Sherman lab, dedicated years of intensive research to make the discovery.

"It's not only showing that the myelin is coming back, but it's causing the axons to fire at a much higher speed," Sherman said. "That's exactly what you want functionally."

The next phase of research involves testing, and potentially refining, the compound in macaque monkeys who carry a naturally occurring version of MS called Japanese macaque encephalomyelitis. The condition, which causes clinical symptoms similar to multiple sclerosis in people, is the only spontaneously occurring MS-like disease in nonhuman primates in the world.

COLUMBUS, Ohio - Suicide is becoming more common in America, an increase most pronounced in rural areas, new research has found.

The study, which appears online today (Sept. 6, 2019) in the journal JAMA Network Open, also highlights a cluster of factors, including lack of insurance and the prevalence of gun shops, that are associated with high suicide rates.

Researchers at The Ohio State University evaluated national suicide data from 1999 to 2016, and provided a county-by-county national picture of the suicide toll among adults. Suicide rates jumped 41 percent, from a median of 15 per 100,000 county residents in the first part of the study to 21.2 per 100,000 in the last three years of the analysis.

Suicide rates were highest in less-populous counties and in areas where people have lower incomes and fewer resources. From 2014 through 2016, suicide rates were 17.6 per 100,000 in large metropolitan counties compared with 22 per 100,000 in rural counties.

In urban areas, counties with more gun shops tended to have higher suicide rates. Counties with the highest suicide rates were mostly in Western states, including Colorado, New Mexico, Utah and Wyoming; in Appalachian states including Kentucky, Virginia and West Virginia; and in the Ozarks, including Arkansas and Missouri.

"While our findings are disheartening, we're hopeful that they will help guide efforts to support Americans who are struggling, especially in rural areas where suicide has increased the most and the fastest," said lead researcher Danielle Steelesmith, a postdoctoral fellow at Ohio State's Wexner Medical Center.

"Suicide is so complex, and many factors contribute, but this research helps us understand the toll and some of the potential contributing influences based on geography, and that could drive better efforts to prevent these deaths."

Suicide rates are trending higher despite a national prevention effort that kicked off in 2015 with the goal of reducing suicide rates 20 percent by 2025. Another recent analysis found that suicide rates in almost 90 percent of U.S. counties increased more than 20 percent from 2005 to 2015.

The new study included 453,577 suicides by adults 25 to 64 years old from 1996 to 2016. Suicides were most common among men and those 45 to 54 years old.

Suicide prevention can be bolstered with this new information about trends and patterns of suicide, said Cynthia Fontanella, a study co-author and associate professor of psychiatry and behavioral health at Ohio State.

"For example, all communities might benefit from strategies that enhance coping and problem-solving skills, strengthen economic support and identify and support those who are at risk for suicide," Fontanella said.

"The data showing that suicides were higher in counties with more gun shops - specifically in urban areas - highlights the potential to reduce access to methods of suicide that can increase the chances an at-risk person will die."

Another factor related to increased suicide rates, particularly in rural areas, was "deprivation," a cluster of factors including underemployment, poverty and low educational attainment.

Long-term and persistent poverty may be more entrenched and the economic opportunities for individuals more limited in rural areas, Steelesmith said, adding that many rural Americans rely on jobs in agriculture and industries including coal mining.

"In cities, you have a core of services that are much easier to get to in many cases. You may have better access to job assistance, food banks and nonprofits that might all contribute to less desperation among residents," Steelesmith said.

High social fragmentation - which factors in levels of single-person households, unmarried residents and the impermanence of residents - was associated with higher suicide rates, as was low social capital, a measure of the interconnectedness of people in an area. Both of these were particularly pronounced in rural America.

Other factors associated with higher suicide rates included high percentages of veterans in a county and lower rates of insurance coverage.

Fontanella said that people who live in rural America might particularly benefit from strategies to promote social connections through community engagement activities that offer opportunities for residents to interact and to become familiar with supportive resources in their area.

Steelesmith said it's important to note that county-by-county geographical information on suicide doesn't tell the whole story. Some states, particularly in the West, have large counties with great variability in terms of resident life experiences, for instance. This work also excludes data on suicides by young and elderly Americans.

Bottom Line: A study of nearly 9,800 Fire Department of the City of New York (FDNY) male firefighters suggests an association between greater exposure to the World Trade Center disaster and long-term cardiovascular disease risk, while the results of other studies have been mixed. This study used two measures of exposure to the World Trade Center disaster (arrival time and work duration at the site) to examine the primary outcome of long-term risk of cardiovascular disease, which included heart attack, stroke, unstable angina, coronary artery surgery or angioplasty, or death from cardiovascular disease. Study authors report 489 primary outcomes among the 9,796 male firefighters in more than 16 years of follow-up. Both acute exposure (arriving at the site on the morning of the 9/11 attacks) and repeated exposure during six or more months of work at the site appear to be associated with higher risk of cardiovascular disease compared with those firefighters who arrived later and worked for less time at the site. The associations were statistically significant after accounting for well-established risk factors of cardiovascular disease. Limitations of the study include that the risk of long-term cardiovascular disease in these firefighters could be attributed to their stressful jobs and exposure to smoke and dust in subsequent fires. The authors suggest the findings reinforce the importance of long-term health monitoring for survivors of disasters like the 9/11 attacks on the World Trade Center.

Authors: Rachel Zeig-Owens, Dr.P.H., M.P.H., and David J. Prezant, M.D., of the Fire Department of the City of New York, and coauthors

(doi:10.1001/jamanetworkopen.2019.9775)

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

Bottom Line: Most transgender and gender-nonbinary teens in China who participated in a national survey study reported abuse, neglect or bullying at home and in school, which the researchers suggest may be due in part to the socially conservative values prevalent in the country.  The study included 385 adolescents (average age nearly 17) who responded to an online survey. Among the 319 teens who reported their parents knew their gender identity, 92% reported experiencing parental abuse or neglect and, among all the teens, 76.6% reported abuse or bullying at school from classmates or teachers. Limitations of the study include that survey questionnaires were only accessible to teens with internet access and all the study measures were self-reported and done over the internet.

Authors: Runsen Chen, M.Sc., M.B.M.S., of the National Clinical Research Center for Mental Disorders, Beijing Key Laboratory of Mental Disorders and Advanced Innovation Center for Human Brain Protection, Beijing Anding Hospital, Capital Medical University in Beijing, and coauthors

(doi:10.1001/jamanetworkopen.2019.11058)

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

September 6, 2019--BRONX, NY--A new study of New York City firefighters has found that exposure to 9/11 World Trade Center (WTC) dust is associated with a significantly increased long-term risk of cardiovascular disease (CVD). The study, conducted by researchers at Albert Einstein College of Medicine, Montefiore Health System, and the Fire Department of the City of New York (FDNY), found that those who arrived first at the WTC site--when the air-borne dust was thickest--have a 44% increased risk of CVD compared to those who arrived later in the day. The study was published online today in JAMA Network Open.

"The increase in risk was significant, even taking into account known CVD risk factors such as age, hypertension, elevated cholesterol, diabetes, and smoking," said study leader David J. Prezant, M.D., a professor of medicine at Einstein, a pulmonary disease specialist at Montefiore, and chief medical officer of the FDNY.

This study's finding of an increased risk of CVD with WTC exposure--as well as the researchers' earlier studies identifying an increased risk for autoimmune rheumatologic diseases and for a blood cancer precursor that can lead to the cancer multiple myeloma--"highlights the need to add these health conditions to the list of WTC-related diseases that are coverable under the James L. Zadroga 9/11 Health and Compensation Act," Dr. Prezant added.

Studies have repeatedly shown that WTC exposure is associated with immediate and long-term risk of adverse health effects, including respiratory problems, post-traumatic stress disorder (PTSD), and several types of cancer. A few studies have examined the association between WTC exposure and CVD. However, the results were inconsistent for a variety of reasons, primarily because they relied on first responders' self-reported health measures.

Assessing Cardiovascular Disease Risk

The current study involved 9,796 firefighters who worked at the WTC site. Most were never smokers (74%) and non-Hispanic white (94%), with an average age of 40 on September 11, 2001. All were men, since there were too few female firefighters at the WTC site to obtain meaningful data.

For this study, the firefighters were divided into four groups: (1) those who first arrived at the WTC site during the morning of 9/11 (who were believed to receive the highest dust exposure); (2) those who first arrived that afternoon; (3) those who first arrived on September 12; and (4) those who first arrived between days 3 and 14.

The researchers reviewed 16 years of medical records, physician examinations, and questionnaires to assess the participants for primary and secondary CVD events. (Primary CVD events were defined as myocardial infarction, stroke, unstable angina, coronary artery surgery or angioplasty, or CVD death; secondary events included transient ischemic attack, angina defined as either angina medication or cardiac catheterization without intervention, cardiomyopathy, and "other CVD": aortic aneurysm, peripheral arterial vascular intervention, and carotid artery surgery.)

Firefighters who arrived during and immediately after the WTC collapse (group 1) had a 44% higher risk of experiencing primary and secondary CVD events compared with those who arrived on September 12 or later (groups 3 and 4 combined). Similarly, those who worked at the WTC site for six months or more were 30% more likely to have experienced a primary or secondary CVD event compared with those who worked less time at the site. These associations were statistically significant after taking into account age, race/ethnicity, and baseline assessments of body mass index, hypertension, elevated cholesterol, diabetes, smoking, and probable PTSD.

"An important message is that new chest pain in this group should not automatically be attributed to well-known WTC-related illnesses, such as acid reflux or obstructive airway disease. It might very well be associated with CVD," said Dr. Prezant.

Monitoring Symptoms and Health

"Our results emphasize why it is crucial to monitor the long-term health of anyone exposed to massive environmental disasters, even many years after the event," said co-lead author Rachel Zeig-Owens, Dr.P.H., a research assistant professor of epidemiology & population health at Einstein and an epidemiologist at Montefiore and FDNY. "By screening for and treating the other CVD risk factors--such as elevated cholesterol, hypertension, obesity, and smoking--we are able to lower the overall risk of CVD in those most exposed to the World Trade Center disaster."

Many other studies have linked both acute and prolonged exposure to air pollution to CVD. The researchers noted that exposure to dust and products of combustion could have triggered persistent disease processes involving chronic inflammation that increased the risk for CVD years later.

Parents should help their children with better sleep patterns, along with any problem behavioural issues, because this can lead to severe insomnia in middle age, a groundbreaking new study shows.

Published in JAMA Network Open journal today, Australian researchers have used data from a long-running UK population study to find links between moderate to severe childhood behavioural problems and insomnia in adults by the age of 42 years old.

Insomnia is the most common sleep disorder in adults, estimated to affect almost one in three people. Chronic insomnia is associated with an increased risk of mental health and other health, wellbeing and economic consequences including working capacity.

"This study shows a consistent association of behavioural problems during childhood, particularly at ages 5 and 10 years, with insomnia symptoms in adulthood," says senior author Flinders University's Robert Adams, Professor of Respiratory and Sleep Medicine at the Adelaide Institute for Sleep Health (AISH) - a leading Australian research centre.

"The findings suggest that early intervention to manage children's externalised behaviours, such as bullying, irritability or constant restlessness, may reduce the risk of adult insomnia.

"As well as identifying sleep problems early in life, we should also identify children with moderate to severe behavioural problems that persist through childhood as potential beneficiaries of early intervention with a sleep health focus," Professor Adams says.

"This study is the first to our knowledge to suggest an unfavourable association between early-life behavioural problems in children and addressing insomnia, from a life-long perspective," says Flinders University lead author, Dr Yohannes Adama Melaku.

"Given the cost of sleep disorders, including insomnia, to every economy and society in the world, it's another important step towards managing this endemic problem in the community," he says.

"This first study is important because we don't know exactly the childhood or early-life factors that potentially influence this outcome of insomnia and finding these connections could reduce sleep disorders in the future."

The United Kingdom 1970 Birth Cohort Study is a large-scale study of more than 16,000 babies born in a single week. The current study includes people from the cohort aged 5 (8550 participants), 10 (9090 people) and 16 years (7653) followed up to age 42 years (2012). Statistical analysis was performed from February 1 to July 15, 2019.

The Flinders University study focused on externalised behavioural problems reported by parents, including cases of restlessness, disobedience, fighting, bullying, property damage and theft and irritability.

The research team's next paper will focus on the effect of maternal smoking during pregnancy and childhood and any impact on insomnia and related sleep issues in adults.