Culture

Research linking economic conditions and health often does not consider children's mental health problems. In a new Health Economics study, investigators found that U.S. children's mental health worsened as the economy weakened. The use of special education services for emotional problems also rose when economic conditions worsened.

The study, which drew on data from the 2001-2013 National Health Interview Survey, found that the effects of economic conditions on children's mental health were comparable regardless of whether investigators measured economic conditions via unemployment rates or housing price indices. In addition, the effects were seen across sexes and ages (4-11 and 12-17 years of age).

"Along with providing new insight into the determinants of child mental health, our results have implications for policy responses to poor economic conditions. We confirm that the consequences of a bad economy extend beyond labor market participants," the authors wrote. "These spillover effects to child mental health suggest that policy responses to weak economic conditions may have larger effects than anticipated. Interventions like extending unemployment benefits to cushion the loss of income, for example, may have benefits for child health that get overlooked."

To treat large gaps in long bones, like the femur, which result from bone tumor removal or a shattering trauma, researchers at Penn Medicine and the University of Illinois at Chicago developed a process that partially recreates the bone growth process that occurs before birth. A bone defect of more than two centimeters is considered substantial, and current successful healing rates stand at 50 percent or less, with failure often resulting in amputation. The team hopes that their method, which they've developed in rodent models to mimic the process of rapid fetal bone growth, can substantially improve success rates. Their findings are published in Science Translational Medicine.

"When bones are originally formed in the embryo, they're first generated from cartilage, like a template," said senior author Joel Boerckel, PhD, an assistant professor of Orthopaedic Surgery and Bioengineering at the University of Pennsylvania. "In order to regenerate bone within defects that otherwise won't heal in grown people, we are seeking to recreate the embryonic bone development process."

To do that, the researchers' process begins with the delivery of specially engineered stem cells (called a condensation of mesenchymal cells) to the rodents' bone defect, which sparks endochondral ossification, the specific term for embryonic bone development.

But, the researchers note that a baby's movement in the womb is also an important factor in the process to develop new bone quickly. Therefore, the second step taken by the team to mimic bone development involved special orthopaedic plates that can be adjusted to vary the mechanical forces placed on the regenerating limbs. This allowed for some movement in the defect area that contributed to cartilage formation and blood vessel growth, key steps of endochondral ossification. Through this combination of development-like stem cell delivery and mechanical forces, bone regeneration was on par with current methods for healing defects, such as high doses of the growth factor, BMP-2, a potent protein that stimulates bone formation. However, this experimental process did not generate any of the typical adverse side effects, such as abnormal bone growth, that can result from using BMP-2.

While plates are currently used to fix serious defects, they keep the joints completely stiff and don't allow for mechanical loading. In this study, the researchers compared stiff plates to those that were "unlocked" to allow limited movement. While bone volume increased in bones that were always kept in the stiff plates, the plates that were unlocked generated far more bone growth as time went on.

"Very little has been known about how the mechanical environment in bone defects affects the capacity of transplanted cells to contribute to the regeneration of the defects," said senior author Eben Alsberg, PhD, the Richard and Loan Hill Professor of Bioengineering and Orthopaedics at the University of Illinois at Chicago. "In this work, we've shown how critically important mechanical forces are in this process when implanting stem cell condensation constructs."

Not only did the researchers look at plates that were unlocked, they also studied the differences that occurred when plates were unlocked. One set was unlocked about four weeks after they were put in place, while the others were unlocked immediately. At 12 weeks after the plates were put in place, the bone growth for plates unlocked a month in was triple that of the plates that remained stiff the entire time. For plates unlocked immediately, the bone growth was doubled what resulted from using stiff plates.

"While this work is in its early stages, it is possible that these finding could influence how non-healing bone defects are treated with respect to both fixation and other transplanted therapeutic strategies," said Alsberg.

Moving forward, the researchers feel that further preclinical studies will be required to determine how these this process and the findings therein can be used in clinic. Additionally, the long-term goal is to not only map development and regeneration processes for bones themselves, but other tissues where the potential for regeneration is limited, such as in cartilage for patients with osteoarthritis.

"Devices and techniques we develop out of this research could also influence the way we implement physical therapy after injury," Boerckel explained. "Our findings support the emerging paradigm of 'regenerative rehabilitation,' a concept that marries principles from physical therapy and regenerative medicine. Our goals are to understand how mechanical stimuli influence cell behavior to better impact patient outcomes without additional drugs or devices."

Like fishermen, Rice University bioengineers are angling for their daily catch. But their bait, biomolecules in a hydrogel scaffold, lures microscopic stem cells instead of fish.

These, they say, will seed the growth of new tissue to heal wounds.

The team led by Brown School of Engineering bioengineer Antonios Mikos and graduate student Jason Guo have developed modular, injectable hydrogels enhanced by bioactive molecules anchored in the chemical crosslinkers that give the gels structure.

Hydrogels for healing have until now been biologically inert and require growth factors and other biocompatible molecules to be added to the mix. The new process makes these essential molecules part of the hydrogel itself, specifically the crosslinkers that allow the material to keep its structure when swollen with water.

Their work, reported in Science Advances, is intended to help repair bone, cartilage and other tissues able to regenerate themselves.

Best of all, the Rice lab's customized, active hydrogels can be mixed at room temperature for immediate application, Mikos said.

"This is important not only for the ease of preparation and synthesis, but also because these molecules may lose their biological activity when they're heated," he said. "This is the biggest problem with the development of biomaterials that rely on high temperatures or the use of organic solvents."

Experiments with cartilage and bone biomolecules showed how crosslinkers made of a soluble polymer can bond small peptides or large molecules, like tissue-specific extracellular matrix components, simply by mixing them together in water with a catalyst. As the injected gel swells to fill the space left by a tissue defect, the embedded molecules can interact with the body's mesenchymal stem cells, drawing them in to seed new growth. As native tissue populates the area, the hydrogel can degrade and eventually disappear.

"With our previous hydrogels, we typically needed to have a secondary system to deliver the biomolecules to effectively produce tissue repair," Guo said. "In this case, our big advantage is that we directly incorporate those biomolecules for the specific tissue right into the crosslinker itself. Then once we inject the hydrogel, the biomolecules are right where they need to be."

To make the reaction work, the researchers depended on a variant of click chemistry, which facilitates the assembly of molecular modules. Click chemistry catalysts don't usually work in water. But with the helpful guidance of Rice chemist and co-author Paul Engel, they settled on a biocompatible and soluble ruthenium-based catalyst.

"There's one specific ruthenium-based catalyst we can use," Guo said. "Others are often cytotoxic, or they're inactive under aqueous conditions, or they might not work with the specific kind of alkyne on the polymer.

"This particular catalyst works under all those conditions - namely, conditions that are very mild, aqueous and favorable to biomolecules," he said. "But it had not been used for biomolecules yet."

Invading predators can devastate an ecosystem. In fact, a leading cause of extinction is the introduction of predators into an isolated system like an island or a lake. The destruction is usually blamed on the predator's eating choices, but sometimes the key lies in the prey animals' responses, according to an international team of researchers led by Princeton's Robert Pringle.

"You really can't understand predator-prey interactions -- or how predators will affect biodiversity and ecosystems -- without understanding the behavior of the prey," said Pringle, an associate professor of ecology and evolutionary biology. "The ways in which prey change their behavior to avoid getting eaten is a hard thing to predict, but without understanding that, you can't predict anything else. Most theory in ecology simply assumes that predators eat prey, end of story. The real world is more complicated. But it's not so complicated that we can't get to the bottom of it."

The question is rapidly becoming more pressing, noted co-author Rowan Barrett, the Canada Research Chair of Biodiversity Science at McGill University in Montreal, Quebec. "Human activity is increasing the occurrence of new predators being introduced to formerly isolated ecosystems," he said. "Our work shows that the consequences of these predator invasions for biodiversity can depend strongly on changes in prey behavior that alter the way prey species use their environments."

To tackle the question, the team used three lizard species: one predator, the curly-tailed lizard Leiocephalus carinatus, and two prey species, green anoles (Anolis smaragdinus) and brown anoles (Anolis sagrei). Their results appear in the June 6 issue of Nature.

The researchers traveled to 16 small islands in the Bahamas that they used as experimental ecosystems. The brown anoles were established on all 16, and the researchers introduced the other two lizards separately or in combination.

"It's so rare in ecology to be able to manipulate whole ecosystems -- these little islands are kind of like big oceanic petri dishes that enable us to run really tight and compelling experiments," Pringle said. "It's just not possible to do that in most places."

The researchers found that in the absence of predators, the two anole species coexisted just fine, with green anoles in trees and brown anoles living closer to the ground. The two species competed for insects, but the competition was "not severe," Pringle said. But when the team introduced the curly-tailed predators, the brown anoles fled to the trees, where the chunky ground-dwelling lizard couldn't follow. This intensified the competition between the two prey species for space and food, which undermined their ability to coexist. The results suggest that when prey can respond rapidly to the presence of a predator by changing their behavior, predators might typically reduce the ability of prey species to coexist.

"One of the key implications of our study is that the size of the refuges that prey have from predators can be really important for ensuring that prey don't go extinct," said Todd Palmer, a co-first-author at the University of Florida. "When there's not enough room for prey to hang out without the constant risk of being eaten, something's got to give, and that's when we see species disappearing. Some of the more recent examples of catastrophic species extinction, such as the collapse of a really diverse group of fish species in the African great lakes, may have occurred in part because there simply wasn't enough safe space in those ecosystems. So our findings not only give us some clues about how to manage future predator introductions, but also a better understanding of how past extinctions may have arisen as well."

This research "provides a beautiful counterexample to a classic ecology theory," said Gaku Takimoto, a theoretical ecologist at the University of Tokyo who was not involved in the research. "In theory, predation promotes the coexistence of competing prey species by crushing superior competitors and siding with inferior competitors, but their experiment showed that risk of predation caused a superior competitor to shift its habitat to usurp that of weaker competitors and destroy their coexistence."

Scientists have long known how important "keystone predators" can be for healthy ecosystems. According to the keystone predator theory, top predators can prevent any one prey species from becoming too abundant and outcompeting all the other prey species, which should generally increase the diversity of the species at low levels of the food chain. While this study does not overturn this concept, it does highlight that an ecosystem with a top predator will not necessarily be more diverse than one without a top predator.

"Predators can reduce the diversity of prey species," said Pringle. "That's not 'good,' and it's not 'bad' -- it is what it is. The important thing to me is that we understand how and why predators have the effects that they do, so that we can predict what will happen when ecosystems gain new predators through invasions or when they lose existing predators through extinctions. That is really what our study was aiming to do. It's not a morality play. There's no good and no evil. We're just trying to get a clear understanding of the biology."

Scientists still don't fully understand all the ways introduced predators affect resident prey species. In some cases, of course, an introduced predator can devastate prey populations by simply eating them up. But prey can also respond to predators in ways that reduce their likelihood of getting eaten -- like hiding in trees, as the brown anoles did. There, the risk of predation is low, but then these areas become crowded, and competition becomes intense. This leads to the opposite outcome from the classical keystone predation scenario; Pringle's team called it "refuge competition."

"After six years of population monitoring, we found that curly-tailed lizards destabilized coexistence of the competing prey species by forcing brown and green anoles to share the same predator-free refuges and intensifying competition between them, leading to the extinction of some populations," said McGill's Barrett. Their results therefore challenge the generality of the keystone-predation hypothesis and support the refuge-competition hypothesis in this environment, he said.

The researchers wanted to dig deeper than simple population surveys, so they conducted DNA metabarcoding on fecal samples from each lizard species, to analyze their diets. DNA metabarcoding, a powerful tool that uses short fragments of fecal DNA to identify the prey species eaten by a predator, showed how the lizard species were competing for food on the islands. The researchers also used stable-isotope analysis to analyze how the experimental treatments affected the length of the food chains on the islands and the position of each species in the food chain.

Taken together, these techniques allowed the researchers to understand their results much more deeply, said Pringle. "A lot of times, you'll run an experiment in the field and get some results, but you won't necessarily understand why you got those results -- you might have a best guess or a favored hypothesis, but it's often a bit ambiguous," he said. "It's been a goal of mine for a long time to integrate new techniques like DNA metabarcoding with established techniques like muddy-boots field experiments to try to get more insight into mechanism. In this study, we really wove all these elements together over the course of the six-year experiment, and that is very satisfying."

Pringle shares co-first-authorship with Tyler Kartzinel, a former postdoc in his lab who is now at Brown University, and with Todd Palmer of the University of Florida. Other Princeton co-authors are graduate student Matthew Hutchinson and graduate alumni Tyler Coverdale (Ph.D. 2018) and Josh Dakin (Ph.D. 2017). Undergraduate Lauren Wyman (Class of 2014) contributed to the fieldwork, and she and Annie Ferlmann (Class of 2016) both did senior theses using data from this project.

"Dr. Pringle was able to mimic naturally occurring introductions of new competitors and predators and then track what happens in real time," said Jodie Jawor, a program director at the National Science Foundation, which funded this research. "This is a rare and valuable test of what happens to communities when new species are introduced. ... Habitats and the composition of animal communities can change for various reasons -- natural disasters, development, construction -- so this work helps us understand the ecological impacts and potentially address them proactively and more fully informed."

Consumers who get a web-based product or mobile app for free are more likely to give it a word-of-mouth boost than a product they buy, suggesting they feel "one good turn deserves another."

That's according to new research from the McCombs School of Business at The University of Texas at Austin by Wen Wen, an assistant professor of information, risk and operations management. She collaborated with the Georgia Institute of Technology's Samuel Bond and West Virginia University's Stephen He on the study, which was recently published in the Journal of Marketing Research.

Offering apps and games for free has become a staple of online service providers. Consumers are given the opportunity to download a free product or platform, often as a potential hook into an eventual upgrade to a higher-tier paid version.

The researchers analyzed more than 5,000 mobile apps, in addition to surveying consumers and conducting experiments using a hypothetical product and a real one. They concluded that consumers are motivated to thank the producers of the free products by sharing positive reviews (both online and face-to-face).

"Consumers of free products, but not paid products, will be motivated to 'return the favor' they have received from producers, and they will share their experience with others as a means of doing so," Wen said.

The researchers also found that consumers feel less risk when trying a free product and are less likely to feel disappointed if the product does not meet their expectations than when they make an investment in a paid product.

Consumers of paid products who share reviews of their purchases have different motivations for doing so, the study said. For them, informing others, especially when little has been said about the product and the reviews are mixed, is the primary reason to weigh in about their experiences with the product.

For marketers, the research offers several key insights. "Our findings reveal important differences in consumer motivation between free- and paid-product settings, driven by differences in perceived obligations to producers and to other consumers," Wen said.

With that in mind, marketers of free products might want to consider embedding "reciprocity cues," such as alerts that tell customers to "spread the word" or "tell your friends," she said.

By the same token, marketers can encourage word-of-mouth for paid products by hinting that it could help other shoppers looking to buy the product. Those marketers, Wen said, could use phrases such as "save them time," "help them choose" and "save them money."

"Speaking for 'Free': Word of Mouth in Free- and Paid-Product Settings" is published in the Journal of Marketing Research.

A new study led by researchers at Woods Hole Oceanographic Institution (WHOI) and Swansea University Medical School furthers our knowledge of viruses--in the sea and on land-- and their potential to cause life-threatening illnesses. Their findings, which examine newly-identified genes carried by mysterious "giant" viruses, could represent potential new drug targets for giant viruses linked to human diseases. The work published this week in Proceedings of the National Academy of Sciences.

An international team of researchers team searched more than 8,000 virus genomes and found that many newly-discovered giant viruses contain multiple genes for a type of enzyme called cytochrome P450. P450 enzymes are common in animals, plants and bacteria, but finding them in new viruses is unexpected. Prior to the giant viruses, it was never considered that viruses would have these genes.

"This is an extremely interesting finding," says biologist John Stegeman, senior author of the paper and the director of the Woods Hole Center for Oceans and Human Health at WHOI. "In animals, P450 enzymes metabolize drugs, make steroid hormones, and defend against pollutants. We have yet to find out what they are doing in these viruses, but for sure they are unique, unlike P450s in any other organism."

P450 enzymes, which constitute one of the largest enzyme superfamilies known, may also have major implications for understanding chemical effects both in the sea and in human disease processes.

"We know some giant viruses may be linked to some forms of pneumonia, so gaining a better understanding of them will help us to develop ways of tackling those viruses," explains David Lamb, lead author from Swansea University Medical School in Wales, who was working on the research while at WHOI on a Fulbright Scholarship.

"The P450s could represent drug targets for giant viruses thought to contribute to some pneumonias," says Stegeman.

Finding P450 genes and enzymes in diverse viruses opens a new window on the evolution of these important enzymes, which may help in understanding the biology and the origin of the giant viruses themselves, which currently is unknown, and hotly debated, Stegeman says.

Viruses are the most numerous biological 'entities' on Earth, though giant viruses were not known until 2003, when a virus large enough to be seen with a light microscope was discovered. More than 1,000 genes were identified in that first giant virus; by comparison, the influenza virus has 14 genes. Since then, additional giant viruses with many more genes, and more P450s, have been found worldwide, some with nearly 3,000 genes. Increasingly, giant viruses are being found in the oceans, including in the deep sea.

Skin cancer is the most common type of cancer in the United States. If you could visibly see signs of skin cancer on your body, would you be more likely to visit the doctor? A group of professors from BYU and the University of Utah asked that exact question as they looked for the most effective ways to influence people to screen themselves for cancer.

The team found that visual stimulation had a significant impact on those whom they studied, a group of more than 2,200 adults ages 18-89 from across the country. The results demonstrate that UV skin damage visuals can cause viewers to feel fear, which then made these individuals more likely to participate in positive sun-safe behaviors such as wearing sunscreen or protective clothing.

"Just talking about skin cancer, being inundated with facts and mortality rates, all of that is fear-inspiring language, but the images were so powerful that they moved people to intend to take action," said Kevin John, an assistant professor in BYU's School of Communications and study co-author.

The group tested a variety of methods including showing people facts, stock photos of other people in the sun, photos where moles have been removed, etc. In total, they used 60 different variations to figure out what method was the most effective.

In addition to sharing facts and figures, John and his colleagues were able to take special UV photos using a VISIA UV complexion analysis system to capture images of skin damage on faces of members from the research team. On the surface, many people may not see signs of skin cancer but with the VISIA UV camera system, UV photographs are capable of revealing existing skin damage caused by UV light exposure which is normally invisible to the naked eye.

"The UV photos, and one particular image of a mole being removed, were the most effective in terms of influencing someone to change their behavior. This tells us these are the types of images we need to use to convince people to screen themselves for cancer. Over time, we hope this will cause mortality rates to drop," John said.

New ALMA observations reveal a never-before-seen disk of cool, interstellar gas wrapped around the supermassive black hole at the center of the Milky Way. This nebulous disk gives astronomers new insights into the workings of accretion: the siphoning of material onto the surface of a black hole. The results are published in the journal Nature.

Through decades of study, astronomers have developed a clearer picture of the chaotic and crowded neighborhood surrounding the supermassive black hole at the center of the Milky Way. Our galactic center is approximately 26,000 light-years from Earth and the supermassive black hole there, known as Sagittarius A* (A "star"), is 4 million times the mass of our Sun.

We now know that this region is brimming with roving stars, interstellar dust clouds, and a large reservoir of both phenomenally hot and comparatively colder gases. These gases are expected to orbit the black hole in a vast accretion disk that extends a few tenths of a light-year from the black hole's event horizon.

Until now, however, astronomers have been able to image only the tenuous, hot portion of this flow of accreting gas, which forms a roughly spherical flow and showed no obvious rotation. Its temperature is estimated to be a blistering 10 million degrees Celsius (18 million degrees Fahrenheit), or about two-thirds the temperature found at the core of our Sun. At this temperature, the gas glows fiercely in X-ray light, allowing it to be studied by space-based X-ray telescopes, down to scale of about a tenth of a light-year from the black hole.

In addition to this hot, glowing gas, previous observations with millimeter-wavelength telescopes have detected a vast store of comparatively cooler hydrogen gas (about 10 thousand degrees Celsius, or 18,000 degrees Fahrenheit) within a few light-years of the black hole. The contribution of this cooler gas to the accretion flow onto the black hole was previously unknown.

Although our galactic center black hole is relatively quiet, the radiation around it is strong enough to cause hydrogen atoms to continually lose and recombine with their electrons. This recombination produces a distinctive millimeter-wavelength signal, which is capable of reaching Earth with very little losses along the way.

With its remarkable sensitivity and powerful ability to see fine details, the Atacama Large Millimeter/submillimeter Array (ALMA) was able to detect this faint radio signal and produce the first-ever image of the cooler gas disk at only about a hundredth of a light-year away (or about 1000 times the distance from the Earth to the Sun) from the supermassive black hole. These observations enabled the astronomers both to map the location and trace the motion of this gas. The researchers estimate that the amount of hydrogen in this cool disk is about one tenth the mass of Jupiter, or one ten-thousandth of the mass of the Sun.

By mapping the shifts in wavelengths of this radio light due to the Doppler effect (light from objects moving toward the Earth is slightly shifted to the "bluer" portion of the spectrum while light from objects moving away is slightly shifted to the "redder" portion), the astronomers could clearly see that the gas is rotating around the black hole. This information will provide new insights into the ways that black holes devour matter and the complex interplay between a black hole and its galactic neighborhood.

"We were the first to image this elusive disk and study its rotation," said Elena Murchikova, a member in astrophysics at the Institute for Advanced Study in Princeton, New Jersey, and lead author on the paper. "We are also probing accretion onto the black hole. This is important because this is our closest supermassive black hole. Even so, we still have no good understanding of how its accretion works. We hope these new ALMA observations will help the black hole give up some of its secrets."

In the first days after the tuberculosis (TB) bacteria infect the body, a flurry of immune cells are activated to fight the infection. Now, researchers have identified a master cell that coordinates the body's immune defenses in those crucial early days, according to a new study from Washington University School of Medicine in St. Louis and Africa Health Research Institute in KwaZulu-Natal, South Africa.

The findings, published June 5 in the journal Nature, suggest that bolstering such cells' activity could help prevent the deadly bacteria from gaining a foothold in the lungs and reduce the tens of millions of new infections that occur every year.

"The immune response to the TB bacteria hinges on the early response of this cell, and that opens up a whole new avenue for TB control," said co-senior author Shabaana Abdul Khader, PhD, a professor and interim head of the Department of Molecular Microbiology at the School of Medicine. "Now we can start thinking about ways to target this cell to help the body fight off the bacteria before they get a chance to establish themselves."

According to the World Health Organization, about 1.5 million people died of TB in 2017, making it the most lethal infectious disease worldwide. While a vaccine is available, it only provides good protection against the more severe forms of the disease in young children and is less effective in older children and adults. Despite being widely used, the vaccine has failed to halt transmission of the disease, and a quarter of the world's population is infected with the TB bacteria.

"Positive results from several recent vaccine trials make this an exciting time to be working in TB immunology," said co-senior author Alasdair Leslie, PhD, a faculty member at the Africa Health Research Institute. "The more we can understand about the interaction between the bacteria that cause TB and people, the more chance we have of building on these gains and defeating this deadly epidemic."

Vaccines are designed to warn the immune system about dangerous microbes by presenting bits of such microbes to adaptive immune cells. These cells remember what they've seen and respond rapidly if and when such microbes show up - ideally, before the microbes multiply and cause disease. But in the case of TB, adaptive immunity alone, even when primed by vaccination, may be too slow to protect people.

Khader, Leslie and colleagues - including co-first authors Amanda Ardain, a graduate student in Leslie's lab, and Racquel Domingo-Gonzalez, PhD, and Shibali Das, PhD, both postdoctoral researchers in Khader's lab - studied animals and people to identify the immune cells and proteins that defend the body against the TB bacteria in the first days after infection.

They found that cells known as group 3 innate lymphoid cells (ILC3) play a pivotal role in the first two weeks of infection. ILC3 cells belong to the innate branch of the immune system that detects and responds to foreign invaders in the body. Biologists have long believed that the innate immune system lacks memory for specific microbes, but recent studies suggest that some innate immune cells may have memory.

Experiments showed that within five days after infection, ILC3 cells show up in the lungs, where they release chemical compounds that activate and attract other immune cells. The arriving cells include other innate immune cells - which come loaded with bacteria-killing weapons - as well as adaptive immune cells that direct and enhance the innate immune cells' killing potential. Together, the immune cells surround the bacteria and destroy them.

In mice that lack ILC3 cells, the immune responses are delayed and struggle to get off the ground. The activating chemical compounds are released later, immune cells are slower to arrive at the lungs, the bacteria are not engulfed by immune cells, and consequently, the mice are sicker and have more TB bacteria in the lungs. When the researchers gave ILC3 cells to mice that lacked their own ILC3 cells, it jump-started the immune response, and the bacterial numbers never rose very high.

"These innate lymphoid cells seem to orchestrate all the early downstream immune responses - both innate and adaptive - that you need to control infection," said Khader, who is also a professor of pathology and immunology.

In people and animals sick with TB disease, ILC3 cells congregated in the lungs, especially in immune structures that surrounded and killed bacteria. After people were successfully treated with antibiotics, ILC3 cells became more plentiful in their bloodstream, suggesting that the cells were no longer needed in the lung to fight infection.

Vaccine developers have largely ignored the innate immune system since it is thought to lack the ability to remember specific microbes. But recent studies have shown that innate immune cells may have memory or can be trained to be more effective, thereby fortifying the body's innate immune defenses and providing wide-ranging protection. The vaccine against TB - known as the BCG vaccine - was developed a century ago and designed to target the adaptive immune system. But it is now thought to work partly by training the innate immune system.

"Children who get the BCG vaccine are protected not only against TB but many different infectious diseases and cancer for a few years," Khader said. "They have lower rates of sickness and death from all causes than children who weren't vaccinated. We wouldn't want to replace the BCG vaccine, but we may be able to find a compound that we can use to boost immunity in vaccinated children, when the effects of the BCG start to wear off."

Khader's group has begun screening a set of chemical compounds, looking for ones that enhance ILC3 activity and drive a stronger immune response in the first days after infection.

"It's still an open question whether ILCs in the lung are trainable or have memory and how long the training or memory would last," Khader said. "But if we can train them and get a population of these cells primed and ready to go in the lung, that might be one way we can make a more effective vaccine for TB."

Leslie added, "This study was an outstanding collaboration between scientists in South Africa and the U.S., and perfectly illustrates the power of bringing together expertise across continents to advance TB science."

Scientists at Harvard University and the Broad Institute's Stanley Center for Psychiatric Research have made a major advance in the development of human brain 'organoids': miniature, 3D tissue cultures that model a patient's own brain cells in a dish. Their new method, published in Nature, consistently grows the same types of cells, in the same order, as the developing human cerebral cortex. The advance could change the way researchers study neuropsychiatric diseases and test the effectiveness of drugs.

The genetics behind human neurological disease are complex, with large spans of the genome contributing to disease onset and progression. Studying neurological diseases in other animals gives limited opportunities for relevant discovery, as human brains are quite distinctive.

Organoids offer great promise for studying disease in humans directly. But so far, they have failed in one very important way.

"We might all use our brains differently, but each of us has the same collection of cell types and basic connections," explained senior author Paola Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard and a member of the Stanley Center. "That consistency is crucial and, with very few exceptions, it is reproduced every time the human brain forms in the womb. There are only the smallest differences between us, in terms of the cell types and structures in our brains."

Until now, that has not been the case with organoids. While they do generate human brain cells, each one is unique. That means they cannot be used easily to compare differences between diseased and control brain tissues.

"Organoids have dramatically advanced our ability to study the human developing brain," said Arlotta. "But until now, each one has been its own snowflake, making its own special mix of cell types in a way that could not have been predicted at the outset. We solved that problem."

Building on seminal work led by the late stem cell biologist Yoshiki Sasai, the team created organoids that are virtually indistinguishable from one another - even when grown for longer than six months in the laboratory.

Furthermore, under specific culture conditions the organoids were healthy and able to develop long enough to produce a broad spectrum of cell types normally found in the human cerebral cortex.

These advances mean that brain organoids can now be used as viable experimental systems to study diseases in patient tissues directly, and to compare different drug effects on human brain tissues.

The same cells, the same way

The researchers focused on organoids of the cerebral cortex: the part of the brain responsible for cognition, language, and sensation. The cerebral cortex plays a key role in neuropsychiatric diseases such as autism spectrum disorder and schizophrenia.

"We made organoids from multiple stem cell lines, from both male and female origins - so their genetic backgrounds were different," explained lead author Silvia Velasco, a research scientist at Harvard and the Broad Institute.

Human brain tissues grow very slowly. In this study, after six months the organoids had grown to three millimeters across. In the largest single-cell RNA sequencing experiment in brain organoids to date, the researchers grouped cells based on which genes were expressed at different stages. Using computational models for big data analysis, they compared each group to the cell types that develop in the embryonic cerebral cortex.

"Despite the different genetic backgrounds, we saw that the same cell types were made in the same way, in the correct order and, most importantly, in each organoid," said Velasco. "We were really excited that this model gave us such consistency."

A new way to investigate disease

Using the optimized method from this study, researchers could make organoids from stem cells derived from patients, or engineer cells containing mutations that are associated with specific diseases.

Arlotta's lab is currently exploring autism, using CRISPR/Cas9 gene editing techniques to develop brain organoids specific to the disorder.

"It is now possible to compare 'control' organoids with ones we create with mutations we know to be associated with the disease. This will give us a lot more certainty about which differences are meaningful, which cells are affected, and which molecular pathways go awry," said Arlotta. "Having reproducible organoids will help us move much more swiftly towards concrete interventions, because they will direct us to the specific genetic features that give rise to the disease. In the future, I envisage we will be able to ask far more precise questions about what goes wrong in the context of psychiatric illness."

"In a short time, we have gained a remarkable amount of knowledge about the many different cell types in the human brain," said co-author Aviv Regev, who is a Core Institute Member and Chair of the Faculty at the Broad Institute, as well as co-chair of the Human Cell Atlas project. "That knowledge has given us a foundation for creating models of this incredibly complex organ. Overcoming the problem of reproducibility opens the doors to studying the human brain in ways that would have been thought impossible just a few years ago."

ANN ARBOR, Mich. -- Nearly a third of birthing moms now deliver babies via caesarean section -- and many of them go home with powerful opioid painkillers.

But there's a better way to take care of patients after C-sections to help them heal faster and manage pain without increasing their risk of long-term opioid use, Michigan Medicine researchers say in a new publication in the American Journal of Obstetrics & Gynecology.

Standardized, evidence-based pain management protocols that lessen opioid use have been used successfully at a handful of institutions around the country, including at University of Michigan's Von Voigtlander Women's Hospital. U-M has seen opioid prescription levels for caesarean deliveries drop to nearly the same as vaginal births.

But these care bundles, which involve a set of interventions to improve patient outcomes, need to be more widespread to benefit more birthing moms no matter where they give birth, U-M authors say.

"Cesarean delivery is the most common abdominal surgery in the world. Despite persistent concerns about high cesarean delivery rates internationally, there has been less attention on improving perioperative outcomes for birthing moms," says lead author Alex Peahl, M.D., a U-M obstetrician gynecologist.

"We need to make sure moms are safe in the postpartum period and are receiving the highest quality care possible," she says. "This includes helping patients achieve greater pain control with less opioids."

More effective birth pain management is crucial at a time when there are increasing concerns for higher caesarean rates, maternal mortality and morbidity and risk for persistent opioid use among birthing moms, the authors say.

Research suggests that women are at greater risk of persistent opioid user after the postoperative period if an opioid is prescribed.

Pain control starts early

Authors highlight a pain management protocol called Enhanced Recovery After Surgery, which has more commonly been implemented for other types of surgeries, including hysterectomies, but has been slower to be used broadly for cesarean deliveries. While intended for planned surgeries, authors say there the strategy is effective for unplanned C-sections as well.

ERAS involves a combination of long-acting opioids that last for 18 hours after delivery - reducing the patient's pain immediately after cesarean - and alternating non-narcotic medications around the clock to limit inpatient morphine.

Timing is key

"The goal is to get on top of the pain before the surgery even starts," Peahl says. "Pain is like a mountain. It's much harder to come down once you're at the top."

"We are offering a longer, more even level of pain control to keep patients comfortable through the day. This helps avoid those high peaks of pain that are much harder to come down from quickly and when the most potent painkillers are often used for immediate relief."

Ensuring high quality care after all c-sections

ERAS could also potentially lower health costs by lessening length of hospital stay. Authors note that ERAS protocols have facilitated next day discharge without increase in readmission rates for up to 25 percent of patients leaving the hospital the day after a c-section.

"This is a promising intervention to standardize care for millions of women who undergo a caesarean delivery every year," Peahl says. "We wanted to share evidence for the potential of these strategies improving the quality of care and patient satisfaction, while reducing overall healthcare costs."

While proven to be effective, several barriers may deter wide implementation of opioid-sparing pain methods like ERAS - which may require shifting some elements of care from hospitals to clinics and developing more robust connections between care settings. U-M, for example, is employing new strategies to further improve patients' pain management through educational materials and shared decision making at the time of discharge.

But once implemented, the protocol is simple to follow and has potential to make care teams' jobs managing pain control much easier, Peahl says.

"Not only have these patients just had surgery but they are also new moms," she says. "Helping them recover from surgery and improving their time with their new infants is crucial.

"Standardizing the process and care provided after c-sections is one step to helping ensure that every woman, regardless of demographics or where she lives, receives the same high quality level of care throughout the birth experience."

A new study has surprised the medical world, finding that smoking does not shorten the length of telomeres - a marker at the end of our chromosomes that is widely accepted as an indicator of ageing.

This suggests that adult telomere length should be considered a static biomarker that changes relatively little during adult life.

The meta-analysis of 18 previously collected datasets led by researchers at Newcastle University is published in the Royal Society journal Open Science today.

The researchers chose to focus on smoking simply because there are more data available on the associations between smoking and telomere length than for any other unhealthy behaviour.

The study confirms that while smokers do indeed have shorter telomeres (as many previous studies have shown), importantly, there is no evidence that telomeres shorten faster in smokers compared to non-smokers, as would be predicted if smoking causes telomere shortening. The results suggest that smoking is not responsible for the shorter telomeres observed in adult smokers.

Professor Melissa Bateson from Newcastle University's Faculty of Medical Sciences who led the study said: "The importance of this study is that it forces us to rethink the value of telomere length as a read-out of how our current lifestyles are affecting our bodies. We don't dispute the abundant evidence that smoking is bad for you, but merely the evidence that telomere length is a good way of assessing the biological damage done by smoking and possibly, by extension, other unhealthy behaviours."

This leads to the question of why then do smokers have shorter telomeres? The team of international researchers suggest that a plausible answer to this question is that both telomere shortening and smoking are made more likely by a third variable, possibly exposure to various forms of adversity in early life such as physical and emotional abuse. The Newcastle University team are continuing research into this area.

This finding changes previous scientific understanding of telomere length, a recognised biomarker of increased morbidity and reduced longevity. It was previously believed that telomere length responds dynamically to current adult behaviour, shortening more when we do unhealthy activities such as smoking and perhaps lengthening in response to healthier behaviours. However, this study suggests that adult telomere length should be reinterpreted as a static biomarker that changes relatively little during adult life.

Method

Data were included from 18 longitudinal studies, spanning 10 countries and four continents. The study was made possible by an international collaboration between the researchers involved in all of these original studies making their data available for re-analysis. The combined dataset is the largest of its type and includes data from 12,579 adults (4,678 current smokers and 7,901 non-smokers). The mean age of the participants varies from 26 to 80 years.

The change in participants' telomere length was measured over a follow-up period of around 8.6 years, using measures of telomere length in blood samples taken at the beginning and end of this period.

Professor Bateson added: "For the scientific community it means that measuring changes in adult telomere length may be less useful than previously thought for identifying behaviour that is harmful and for monitoring the consequences of behaviour change.

"More generally, the findings underline the need for caution when interpreting correlational data. Just because two variables are correlated does not mean that one variable causes the other."

Scientists from Trinity College Dublin have discovered how the highly infectious and sometimes deadly Hepatitis C virus (HCV) "ghosts" our immune system and remains undiagnosed in many people. They report their findings today [Wednesday June 5th] in the international FASEB journal.

HCV's main route of transmission is via infected blood but over the past 40 years it has accidentally been given to many patients across the world via infected blood products. The virus replicates particularly well in the liver, and the damage it causes makes it a leading cause of liver disease worldwide.

Even though HCV can be deadly, initial infection is rarely accompanied by any obvious clinical symptoms for reasons that have - until now - remained unknown. As a result, it often goes undiagnosed for the first 6-12 months following infection.

If left untreated HCV spreads throughout the liver, stimulating a low-level inflammatory response. Over several months, these mild responses - accompanied by subsequent liver repair - result in fibrotic scarring of the liver. The liver's main job is to filter out toxins, but during HCV infection the build-up of fibrotic, non-functioning liver tissue, results in reduced liver function. Without a fully functioning liver, one major side-effect is the build-up of toxins, often referred to as "jaundice". If patients do not realise they are infected with HCV, their first noticeable symptoms are the side-effects of liver fibrosis (such as jaundice).

While the majority of HCV infections are now treatable with new medicines, early detection would avoid the damaging progression to liver disease. Therefore, a group of scientists led by Assistant Professor in Immunology at Trinity, Nigel Stevenson, set out to understand how the virus avoids being discovered for months after infection.

HCV suppresses the immune response

Under normal circumstances, our cells communicate with each other with molecules called cytokines, which work by activating specific cascades of other molecules within our cells called signalling pathways. These cytokines and their signalling pathways trigger the expression of hundreds of molecules within our cells to increase inflammation and anti-viral activity. This immune response is capable of killing and clearing viral infections from our cells and bodies.

Uncontrolled inflammation would be dangerous, however, so to ensure our immune response to infection is appropriately regulated, several cytokine signalling pathways are controlled by immune regulators called "Suppressor Of Cytokine Signalling (SOCS)" regulators. After a period of time following an initial response, pro-inflammatory cytokine signalling pathways are shut down by SOCS.

The Trinity scientists found that HCV "ghosts" our immune response, by triggering our own SOCS regulators; a specific part of the virus is responsible for increasing a specific SOCS molecule - in both liver and immune cells.

Dr Stevenson said: "We've discovered that HCV hijacks this regulatory process by causing the expression of SOCS in our cells. By increasing the expression of SOCS, HCV basically dulls the normal immune response to viral infection. Without a strong signal our body's cells cannot then mount an effective inflammatory and anti-viral response that clears infection."

"This ability shields HCV from our body's normal, effective anti-viral immune response and creates a perfect environment in which to survive, replicate and infect other cells. Many diseases are mediated by increasing the inflammatory response to an inappropriately high level, but in this case it is the lack of adequate inflammation that enables HCV to go undiagnosed, leaving it free to rapidly replicate and infect other cells."

U.S. hemp production is soaring, but government oversight hasn't kept up, according to an article in Chemical & Engineering News (C&EN), the weekly newsmagazine of the American Chemical Society. The industry is scrambling to find common ground between states, which each have a different set of rules for hemp growers and processors.

By allowing states to pilot hemp cultivation and commercialization programs, the 2014 U.S. Farm Bill kick-started production of the crop in the U.S. Although the fiber is used to produce textiles, building materials and plastics, most of the increased demand for hemp is driven by the compound cannabidiol (CBD), which is added to many products including gummies, vaping oil, food and cosmetics. Although CBD doesn't produce a "high," some people claim that the compound helps reduce anxiety and pain. Currently, national standards for hemp production, testing and labeling are lacking, Senior Editor Britt E. Erickson writes. Many states only require that the level of tetrahydrocannabinol (THC), the psychoactive substance in cannabis, be less than 0.3%. The lack of testing for CBD-containing products has resulted in inaccurate labeling and inconsistent quality, experts say.

The U.S. Department of Agriculture is working with hemp industry groups to develop rules that regulate labeling standards and product testing. The agency plans to issue the regulations by the 2020 growing season. Also, the FDA has established a task force to examine regulatory options for compounds from hemp, but it is unclear when those regulations will be put into practice. Because some companies refuse to work with hemp industries, which they associate with illegal cannabis, advocates and organizations are hoping to bring about educational programs to dispel the notion that the production and transport of the material are illegal. Meanwhile, other advocates are working to help people recognize the benefits of hemp-derived products.

TORONTO, JUNE 4, 2019 - For children with severe epilepsy, surgery is the last resort used to prevent seizures but the treatment can often come with the risk of both visual and cognitive impairments. Now, a new study funded by the National Eye Institute and jointly led by researchers at York University's Faculty of Health and Carnegie Mellon University, finds that the brains of children with severe epilepsy can compensate by rewiring for missing regions of the visual cortex after surgery.

"What we're seeing is remarkable," said Erez Freud, assistant professor, Department of Psychology in York University's Faculty of Health and Centre for Vision Research, co-lead author of the study. "The most striking case in our findings was a 14-year-old girl who had severe epilepsy that originated from the left side of the brain. The part of the brain that was removed in the surgery is known to mediate the ability to read. Despite this hemisphere being removed, this patient could read with relatively normal functioning and when we scanned her brain using the fMRI we found that this 'reading region' of the brain had re-mapped to the healthy right hemisphere."

Researchers say this provides strong evidence that the brain has some degree of plasticity. In order for the brain to process visuals normally, it needs to process information sent from the eye and the part of the brain that allows it to understand what the eye is seeing (perception). In order for an individual to see, signals from the eye are first processed in the early visual cortex - a region at the back of the brain that is necessary for sight - and then travel through other parts of the cerebral cortex, to allow recognition of patterns, faces, objects, scenes, and words. In adults, even if sight is still intact, injury or removal of even a small area of the brain's vision processing centres can lead to dramatic, permanent loss of perception, making them unable to recognize faces or locations, or to read. But in children, who are still developing, this part of the brain seems to have plasticity and is able to rewire itself.

Tina Liu, former Ph.D student at Carnegie Mellon University, is co-lead author of the study, and Marlene Behrmann, Professor, Department of Psychology, at Carnegie Mellon University, is senior author.

The researchers recruited 10 children who had undergone surgery for severe epilepsy between the ages of six and 17, caused in most cases by an injury such as stroke in infancy or a tumor. The team compared the neural and visuoperceptual profiles of these patients with 10 healthy control children. Three of the children who had gone through a surgery had lost parts of the visual cortex on the right side, three on the left side, and four had lost other parts of the brain not involved in perception, serving as a second kind of control group. Of the six children who had areas of the visual cortex removed, four had permanent reductions in peripheral vision on one side due to loss of the early visual cortex. In each case, the epilepsy was resolved or significantly improved in all children after surgery.

In order to better understand how plasticity could be occurring, researchers conducted the study in two phases. In the first phase, each participant was exposed to different series of tasks that tested the children's perception abilities, including facial recognition, the ability to classify objects, reading, and pattern recognition. They did this by asking the children to identify objects, places and faces. In the second phase, researchers imaged participants' brains using functional magnetic resonance imaging (fMRI scan). Participants were asked to lie down in the MRI and watch a stream of pictures, words, faces, objects and places. The fMRI allowed researchers to accurately visualize areas in the brain that were activated and measure the response to these pictures.

With the exception of two individuals who had greater portions of the cortex altered, researchers found all patients showed normal perceptual performance on tasks and were able to identify faces and objects, places and words, falling within the normal range even for complex perception and memory activities. Even in participants who did not show clear remapping, results showed the healthy region of the brain was still able to compensate for missing regions in the hemisphere of the brain where lesions were removed, and in a way not usually seen in adults. Researchers say these findings offer new insights into the malleability of the cortex in children.

"It's possible that early surgical treatment for children with epilepsy might be what allows this re-mapping," said Freud. "This may be because epilepsy is an on-going condition of the brain and with early removal of the tissue, the brain may have time to rewire itself to the other healthy hemisphere and can therefore compensate for the functions that are impaired in the other part of the brain. But more research is needed to better understand exactly what the developmental processes are that mediate this compensation."

Freud's research is currently funded by the Vision: Science to Applications program at York University.

The study is published in the Journal of Neuroscience.