Culture

Researchers have come up with a new way to image cell populations and their genetic contents. Their study, appearing June 20 in the journal Cell, describes how a technique called DNA microscopy helps illuminate the spatial organization of genetic material within cells and tissues without specialized, expensive optical equipment. Using only the sample itself plus reagents delivered with pipettes, DNA microscopy prompts a specimen to provide spatial information about itself as part of a chemical reaction--the products of which can be read out by DNA sequencing.

If light microscopy can be compared to taking photographs of a city from an orbiting satellite, DNA microscopy is like touring that city at street level, says co-author Joshua Weinstein, a postdoctoral associate at the Broad Institute of Harvard and MIT.

Weinstein, computational and systems biologist Aviv Regev, and neuroscientist and molecular biologist Feng Zhang (@zhangf) have used DNA microscopy to image human cancer cell lines. Their goal is to accurately image long stretches of the highly variable gene sequences found in cancer mutations, immune receptors, immunoglobulin genes, and more.

Understanding how cells interact with one another is critical for advancing biological research and clinical treatments. Despite progress in profiling cells' molecular constituents, spatially mapping these constituents is still machine intensive, relying on either light microscopy or slicing and dissecting.

To understand how DNA microscopy works, imagine constructing a map of cities in the United States based on radio signals between radio towers. Even if each city's radio tower pings only its nearest neighbors, algorithms can compile this incomplete, imprecise data into an accurate map.

In DNA microscopy, a chemical reaction tags short segments of DNA called unique molecular identifiers (UMIs). The UMIs are the radio towers, and the radio signals are clouds of copies of UMIs following the physics of diffusion.

Thanks to the UMIs, the sample being studied is now dotted with chemically discrete points. Tracking the collisions between clouds of UMIs copies--with each collision written into DNA sequence products as a chemical reaction--allows researchers to narrow the uncertainty of original UMI positions. The resulting image is a two- or three-dimensional genetically detailed plot of molecular positions in physical space.

The plot represents hundreds of thousands of dimensions dictated by the number of molecules with which the tagged molecules can plausibly communicate.

"A chemical reaction within the specimen encodes information into DNA from which an algorithm can decode the relative positions of molecules without needing to know in advance cell identity or the nature of genetic variation," Weinstein says.

DNA microscopy's weakness is resolving empty spaces, such as large gaps between two cells plated on a dish. If this can be addressed, the researchers hope to more fully explore miniscule spatial structures in the biological world, revealing layers of information that could be hidden by the limits of optical- and electron-based imaging.

"We believe that the most exciting applications of this technology are in areas of biology in which mutations, RNA editing, and other forms of nucleotide-level variation work hand in hand within the organism to either produce physiological outcomes or cause disease," Weinstein says. Examples include understanding how the immune system develops, how the nervous system is wired, and how genetic mutations are present in tumors and affect their interactions with other cells, including immune cells.

Washington, DC - While the measles vaccine has eliminated the virus in many high-income countries, the global burden of disease persists with an estimated 245,000 measles cases and 68,000 measles-associated deaths worldwide in 2016. India alone accounted for 50 percent of measles cases and 30 percent of measles deaths in 2016. Although low- and middle-income countries (LMICs) account for a large proportion of global measles cases, high-income countries have recently seen a resurgence of measles outbreaks.

According to the US Centers for Disease Control and Prevention (CDC), there have been over 1,000 measles cases reported across 28 states in the US so far in 2019. This is the largest number of cases the country has seen in almost 3 decades, and since measles was eliminated in 2000. Despite these recent setbacks, the highly efficacious and cost-effective measles vaccine prevented an estimated 21.1 million child deaths worldwide between 2000-2017. The vaccine has also been tied to reductions in all-cause childhood mortality and infectious disease morbidity outcomes in LMICs, although little generalizable evidence exists on the early-life receipt of measles vaccines and associated child growth parameters, cognition, and schooling grades.

Researchers examined Z- scores of height-for-age (HAZ), BMI-for-age (BMIZ), weight-for-age (WAZ), scores of Peabody Picture Vocabulary Test (PPVT), early grade reading assessment (EGRA), language and mathematics tests, and highest schooling attainment across ~6,000 measles-vaccinated and unvaccinated children in Ethiopia, India, and Vietnam. Propensity score matching methods were used to reduce the effects of potential confounding factors.

Researchers analyzed survey data from 3 cohorts of children enrolled in the Young Lives Survey (YLS), a longitudinal study assessing childhood poverty. Growth, cognitive, and schooling indicators were evaluated across measles-vaccination groups, and outcomes at ages 7-8 and 11-12 years were compared between children across the 3 countries with reported receipt or non-receipt of measles vaccination at 6-18 months of life.

"We reviewed children who were followed since infancy through childhood and used statistical techniques that produced robust estimates of the associations of measles vaccination with later life outcomes. It is the first and the largest multi-country study of its kind.", said CDDEP senior fellow Arindam Nandi, the lead author of the study.

The study found that at ages 7-8 years, measles-vaccinated children had significantly higher HAZ scores in India (an increase of 0.13 points, P=0.05), and significantly higher BMIZ and WAZ scores in Vietnam (an increase of 0.18 and 0.23 points, P=0.04, 0.01 ) as compared with matched measles-unvaccinated children. Measles-vaccinated children scored 2.3, 2.5, and 2.7 points more on EGRA in Ethiopia, India, and Vietnam, respectively. Vaccinated children scored 4.5 and 2.6 percentage points (pp) higher on PPVT and 2.9 and 4.0 pp higher on mathematics in Ethiopia and Vietnam.

Similarly, at ages 11-12 years, measles-vaccinated children had 0.19 higher BMIZ scores in Vietnam (P= 0.04), and they scored 3 pp more on English and PPVT in India. Vaccinated children also attained 0.2-0.3 higher schooling grades across all ages and countries compared to measles-unvaccinated children.

Findings indicate that measles vaccination at 6-18 months of life is associated with long-term health, cognition, and schooling benefits among children in Ethiopia, India, and Vietnam.

"As a pediatrician and parent myself, I feel confident that these results will show other parents and medical workers how the measles vaccine may help their children achieve better health and educational outcomes.", said Anita Shet, who is a coauthor of the study and a pediatric infectious disease specialist at the International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health.

CDDEP director Ramanan Laxminarayan, a coauthor of the study, said, "At a time when there is hesitation about measles vaccination by parents, the results of this study are an important reminder that the benefits of measles vaccination go beyond child survival and are instrumental in enabling adults who have higher cognitive ability, education and physical stature. These are critical to economic development that every country aspires to."

Microscopy just got reinvented - again.

Traditionally, scientists have used light, x-rays, and electrons to peer inside tissues and cells. Today, scientists can trace thread-like fibers of nerves throughout the brain and even watch living mouse embryos conjure the beating cells of a rudimentary heart.

But there's one thing these microscopes can't see: what's happening in cells at the genomic level.

Now, biophysicist Joshua Weinstein and colleagues have invented an unorthodox type of imaging dubbed "DNA microscopy" that can do just that. Instead of relying on light (or any kind of optics at all), the team uses DNA "bar codes" to help pinpoint molecules' relative positions within a sample.

With DNA microscopy, scientists can build a picture of cells and simultaneously amass enormous amounts of genomic information, Weinstein says. "This gives us another layer of biology that we haven't been able to see."

Weinstein, Howard Hughes Medical Institute (HHMI) Investigator Aviv Regev, and molecular biologist Feng Zhang, who was selected as an HHMI investigator in 2018, report the work June 20, 2019, in the journal Cell.

"It's an entirely new category of microscopy," Regev says. "It's not just a new technique, it's a way of doing things that we haven't ever considered doing before."

Something new

Until now, microscopy fit into two main categories. The first is based on optics; light microscopy, for example, dates back to the 1600s and relies on visible light to illuminate samples. Scientists have riffed on this approach, even going beyond the visible spectrum. Electron microscopes, fluorescence microscopes, light-sheet microscopes ¬- they're all based on the principle that samples emit photons or electrons, and the microscope detects the emission.

The second category is based on dissecting samples at locations defined by a microscope. Computer programs then stitch together each dissected piece into a complete picture of the intact sample. Optical imaging can offer intricate portraits of subcellular structure and action. Dissection-based microscopy can give scientists genetic information.

Weinstein and his colleagues at the Massachusetts Institute of Technology wanted to create a way to do it all in one shot - to take a snapshot of a cell's position and spell out the specific genetic sequences driving it.

That combo is important for scientists studying genetically diverse sets of cells. The immune system is a perfect example, Weinstein says. Immune cell genes can vary down to a single letter of DNA. Each variation can trigger a dramatic shift in the type of antibodies a cell produces. Where that cell is located within a tissue can alter antibody production, too.

If you focus on just one or the other, "you're only getting part of the picture," he says.

How it works

Capturing such a complete picture of a cell doesn't require an expensive microscope or a lot of fancy equipment, Regev says. All you need to get started is a specimen and a pipette.

First, scientists take cells grown in the lab and fix them into position in a reaction chamber. Then, they add an assortment of DNA bar codes. These stick to RNA molecules, giving each a unique tag. Next, the team uses a chemical reaction to make more and more copies of each tagged molecule - a growing pile that expands out from each molecule's original location.

"Picture every single molecule as a radio tower broadcasting its own signal outward," Weinstein says.

Eventually, the tagged molecules collide with other tagged molecules, forcing them to link together in pairs. Molecules located close to one another will be more likely to collide, generating more DNA pairs. Molecules further apart will generate fewer pairs.

A DNA-sequencing machine spells out the letters of every molecule within the sample, which takes up to 30 hours. An algorithm the team created then decodes the data - which, in the paper, represents roughly 50 million DNA letters of genetic sequences from each original specimen - and converts the raw data to images.

"You're basically able to reconstruct exactly what you see under a light microscope," Weinstein says.

The two methods are complementary, he adds. Light microscopy can see molecules well even when they're sparse within a sample, and DNA microscopy excels when molecules are dense - even piled up on top of one another.

He thinks DNA microscopy could one day let scientists speed the development of immunotherapy treatments that help patients' immune systems fight cancer. The method could potentially identify the immune cells best suited to target a particular cancer cell, he says.

Every cell has a unique makeup of DNA letters, or genotype, Zhang says. "By capturing information directly from the molecules being studied, DNA microscopy opens up a new way of connecting genotype to phenotype."

The possibilities with this category of microscopy are wide open, Regev adds. "We hope that it sparks the imagination - that people will be inspired with great ideas that we've never thought about."

Two papers publishing June 20 in the journal Cell show that Egyptian fruit bats and mice, respectively, can "sync" brainwaves in social situations. The synchronization of neural activity in the brains of human conversation partners has been shown previously, as a result of one person picking up social cues from the other and modulating their own behavior based on those cues. These studies now suggest that something similar occurs when animals engage in natural social interactions and find that some aspects of the animals' social behavior can be predicted based on neural observations.

"Animal models are really important for being able to study brain phenomena at levels that we can't normally access in humans," says Michael Yartsev of the Department of Bioengineering at the University of California, Berkeley, and senior author of one of the papers. "Because bats are extremely social and naturally live in highly complex social environments, they are a great model for tackling important scientific questions about social behavior and the neural mechanisms underlying it."

"If you think of the brain like a black box that receives input and gives some kind of output in response, studying social interactions is like trying to understand how the output of one box provides input to another, and how those two boxes work together and create a loop," says Weizhe Hong of the Departments of Biological Chemistry and Neurobiology at the University of California, Los Angeles, and senior author of the other paper. "Our research in mice allows us to peer inside these black boxes and get a better look at the internal machinery."

Previous studies showing how neural activity in humans becomes synchronized during social interactions have used technologies like fMRI and EEG, which look at brain activity with relatively coarse spatial and temporal resolutions. These studies found that when two people interact, structures in their brain simultaneously decode and respond to signals from the other person.

Because the new studies looked at neural activity at a level of detail that is difficult to obtain in humans, they could explore the detailed neural mechanism underlying this phenomenon.

The Berkeley team monitored the bats for sessions of about 100 minutes each as they engaged in a wide range of natural social interactions, such as grooming, mating, and fighting. The bats were filmed with high-speed cameras, and their specific behaviors and interactions were carefully characterized.

As this was happening, the scientists were using a technology called wireless electrophysiology to simultaneously record the brain activity in the bats' frontal cortices across a wide range of neural signals, ranging from brain oscillations to individual neurons and local neural populations. They saw that the brains of different bats became highly correlated and that this correlation was most pronounced in the high-frequency range of brain oscillations. Furthermore, the correlation between the brains of individual bats extended across multiple timescales of social interactions, ranging from seconds to hours. Remarkably, by looking at the level of correlation, they could predict whether the bats would initiate social interactions or not.

The UCLA team took a different tack. They used a device called a miniaturized microendoscope to monitor the brain activities of mice during social situations. These tiny devices, which weigh only two grams, are fitted on the mice and allow the researchers to monitor the activity of hundreds of neurons at the same time in both animals. They saw that mice also exhibit interbrain correlations in natural social interactions where animals freely interact with each other. Moreover, the access to thousands of individual neurons gave them an unprecedented view of both animals' decision-making processes and revealed that interbrain correlation emerges from different sets of neurons that encode one's own behavior and behavior of the social partner.

Social interactions are often nested within the context of a dominance hierarchy. By imaging two mice in a competitive social interaction, they discovered that behavior of the dominant animal drives synchrony more strongly than behavior of the subordinate animal. Remarkably, they also found that the level of correlation between two brains predicts how mice will respond to each other's behavior as well as the dominance relationships that develop between them.

"Natural social interactions are complex," says Wujie Zhang, a postdoctoral researcher in Yartsev's lab and first author of the fruit bat paper. "It is important to embrace this complexity in order to understand real-life social interactions at the neural level."

"We know that social interactions are altered in many mental diseases in human, including autism spectrum disorders and schizophrenia," says Lyle Kingsbury, a graduate student in Hong's lab and first author of the mouse paper. "Developing a genetically tractable model system opens up the possibility of exploring how interbrain synchrony is disrupted in people with these conditions and may provide novel information about possible interventions."

People who are obese from childhood through to middle age are more than twice as likely to have difficulty with daily tasks such as lifting, climbing stairs and carrying shopping by the time they are 50, a new UCL study has found.

The study, published today in the International Journal of Epidemiology, found that those who became obese in early life had more than double the risk of difficulties with such tasks than those who were never obese.

Longer duration of obesity had the most impact on risk, the study found, with those becoming obese in middle age having a smaller increase in risk. For example, men who became obese between the ages of 45 and 50 faced an increase in risk of about 50%, while for women the risk increase was 78%. The authors suggested this was likely because people who were obese for longer were also more likely to have a higher BMI by the age of 50.

Dr Nina Rogers (UCL Epidemiology & Public Health), lead author of the study, said: "The prevalence of obesity at younger ages is increasing. Since obesity in childhood often tracks into adulthood, it is likely that more people will spend increasing periods of their life living with obesity.

"Our study therefore emphasises the importance of preventing and delaying the onset of obesity in order to mitigate the risk of poor physical functioning in middle age."

The researchers analysed data from 8,674 participants from the 1958 National Child Development Study, a birth cohort study that has followed thousands of people from when they were born in 1958 through to midlife.

The study found that obesity at any age in adulthood was associated with greater risk of poor physical functioning at age 50. For example, compared to a woman of average height (1.62cm) and weight at 23 years, an 8kg higher weight was associated with a 32% elevated risk of poor physical functioning at the age of 50.

Physical functioning was assessed with a validated questionnaire that asked participants how able they were to do the physical tasks of daily living such as carrying shopping, bending, kneeling, climbing up stairs and walking moderate distances. The most limited 10 per cent of respondents in each gender were classed as having poor physical functioning.

Half of the participants classified as having poor physical functioning reported that they had trouble bending, kneeling or stooping and just over a quarter had difficulty bathing or dressing.

The authors said that being able to carry out everyday physical tasks, such as those examined, was important as it enabled people to live independently, work or volunteer for longer, and engage more with friends, family and the community around them.

Dr Pinto Pereira (UCL Epidemiology & Public Health), senior author of the study, said: "Adults need to be able to perform the physical tasks of daily living in order to live independently and this is particularly important in the context of an ageing population. Examining physical functioning in middle age is crucial because there may be scope to intervene to delay or possibly reverse poor physical functioning before older ages when problems may be harder to alter."

A genomic strategy implemented by researchers at Baylor College of Medicine can efficiently increase the molecular diagnostic rate of undiagnosed diseases. The researchers report in the New England Journal of Medicine that reanalysis of preexisting molecular data, taking into consideration new disease-causing genes and other genetic knowledge that have been identified since the original analysis, resulted in an increase in the diagnostic yield of cases, nearly doubling it in one of the reanalysis cohorts.

To facilitate the laborious and time consuming reanalysis while still capturing the majority of the diagnoses, the researchers implemented a computational pipeline that helped semi-automate the process. The researchers discuss the value of data reanalysis in providing patients with answers about the causes of their condition and, in some cases, changing disease management and treatment. In addition, since very little bench work is needed and the process is semi-automated, the cost of this reanalysis work is only a fraction of that of the original test.

"In the 2016 meeting of the American College of Medical Genetics, our DNA diagnostic lab was the first to report that systematically reanalyzing molecular data, taking into account new genetic knowledge published since the original analysis, increased the molecular diagnostic rate in two patient cohorts," said first and corresponding author Dr. Pengfei Liu, assistant professor of molecular and human genetics at Baylor and laboratory director of clinical research at Baylor Genetics. "In this work, we have confirmed and added support to our strategy by reanalyzing two cohorts and developing an analytical tool that accelerates the process efficiently and accurately."

Liu and his colleagues reanalyzed exome sequencing data, which refers to the pieces of a person's genomic DNA that contain instructions for making proteins. Analyzing these pieces called exons allows researchers to identify changes, also called variants, in the DNA sequence. Many mutations that cause disease occur in exons, therefore whole exome sequencing is considered to be an efficient strategy to identify candidates for disease-causing mutations.

The researchers reanalyzed exome sequencing data of two patient cohorts, taking into account genetic knowledge published between the date of the original analysis and December 2017. The first cohort of 250 patients had been originally analyzed in 2012 and the second cohort of 2,000 patients in 2013. Manual reanalysis of the exome sequencing data of the first cohort nearly doubled the diagnostic yield - it increased from 25 to 47 percent.

"The reanalysis was very labor intensive and time consuming, which prompted us to design a computational pipeline that would help us semi-automate the process," Liu said. "Reanalysis of the sequencing data of the first cohort with our computational pipeline achieved a diagnostic sensitivity of 92 percent. Our reference was the manual reanalysis."

The researchers then applied the computational pipeline to reanalyze the data of the second cohort of 2,000 patients and also increased the diagnostic rate, in this case to 37 percent from 25 percent.

"For both cohorts, most of the new molecular diagnoses resulted from newly discovered disease genes - 75 percent of the diagnosis from the first cohort and 64 percent from the second cohort," said co-author Dr. Yaping Yang, professor of molecular and human genetics at Baylor. "This strongly supports the value of our strategy."

In addition, Liu and colleagues sent the updated sequencing results to the corresponding physicians of the patients in the cohorts. They also requested feedback from the physicians in the first cohort whose patients' reanalysis had produced a new molecular diagnosis. About 40 percent of the physicians responded. They reported that 75 percent of their patients received genetic counseling for the updated findings, and about half of those patients had their clinical management changed as a consequence of the new results. The patients who did not receive genetic counseling about their updated results had moved, died or did not keep their follow-up appointment.

"Our work suggests that periodic reanalysis may benefit patients, their families and the physicians caring for them," said co-author Dr. James R. Lupski, Cullen Professor of Molecular and Human Genetics at Baylor, principal investigator at the Baylor Hopkins Center for Mendelian Genomics and faculty with the Baylor genetics and genomics graduate training program. "Drs. Liu, Yang and colleagues provide a computational process that demonstrates the feasibility of reducing the work load involved in reanalysis. We hope that other genetic labs, physicians and patients will benefit from this strategy."

Dog attacks have been on the rise and it may the owners who need to go back to school. A new study published in Risk Analysis: An International Journal investigated what leads dog owners to train their pets using positive reinforcement methods.

Positive reinforcement training methods are considered to be the most effective and humane approach to training dogs but many owners fail to effectively implement the technique.

According to the Centers for Disease Control and Prevention, approximately 4.7 million Americans are bitten by a dog each year and, in 2018, there were 36 dog-bite fatalities. Despite the legal liabilities and possible euthanization, many dog owners have not learned how to effectively manage their dog's aggressive behavior.

This study found that perceived effectiveness of positive reinforcement and the owners' level of confidence in their abilities were key factors in the use of such techniques. The researchers--Emma J. Williams and Emily Blackwell, University of Bristol, United Kingdom--also explored the potential role of psychological factors such as the owner's emotional state, social influence, and cognitive biases on the use of positive reinforcement.

The study was designed to test a social science theory called Protection Motivation Theory that suggests focusing attention on owners' appraisal of the threat of dogs' bad behaviors as well as owners' appraisal of the potential efficacy of positive reinforcement. Participants were recruited using an online survey panel and a total of 630 individuals completed the questionnaire.

Perceived confidence (i.e., self-efficacy) in using different reinforcement techniques, including positive reinforcement, when in the home and when in public appear to be the two most influential factors underlying how owners choose to manage their dog's behavior, followed closely by the perceived severity of the behavior (i.e., threat). However, many respondents noted feeling stress and anxiety when their dog behaved badly and reported that this reduced their confidence in their ability to effectively manage their dog's behavior.

Behaviors that owners struggle with might include stiff posture with hackles raised and intense staring, barking, growling, snarling, lunging, snapping, nipping, and/or biting.

The role of self-efficacy suggests that it is not enough to simply tell owners what techniques to use and how to use them. Instead, owners need help feeling that they are able to use the techniques, especially when their dog is acting aggressively.

"This research suggests that people are likely to need practical support when learning to use positive methods. This support should both demonstrate the effectiveness of reward-based training and provide an opportunity for people to practice skills under expert guidance, so that they really feel confident in using the techniques when they encounter challenging scenarios," states Williams. "Importantly, this research also highlights the emotional impact that attempting to manage a reactive dog can have. It is important for owners, and the practitioners helping them, to consider how they can best manage their own well-being and reactions, as well as those of the dog, when navigating their training journey."

Future interventions should focus on increasing owner confidence in the effective implementation of these methods across multiple scenarios, as well as helping owners manage their own emotional responses to a challenging situation. Providing owners both the space and time to practice techniques in diverse environments is likely to assist with developing confidence.

JUPITER, FL -- June 19, 2019 -- Fight or flight, panic, trembling: Our brains are wired to ensure we respond instantly to fear. While that fear response may save our lives in the dangerous moment, at times people stay on high alert long after the threat has passed, and develop post-traumatic stress disorder.

A new study from Scripps Research in Florida suggests it may be possible to disarm the emotional memories of trauma that drive PTSD symptoms. Scripps Research neuroscientist Courtney Miller, PhD, and her team identified a key molecule found elevated within the brain's emotional memory processor, the amygdala. Experiments suggest that suppressing that molecule enables faster recovery from trauma. The molecule may also offer a novel biomarker for treatment.

Writing in the journal Molecular Psychiatry, Miller discovered that trauma elevates a specific microRNA in an area of the brain where long-term memories of fear reside, the basolateral amygdala complex. They found the microRNA, called mir-135b-5p, altered in both stress-conditioned mice and in military veterans who had been diagnosed with PTSD following deployment in Afghanistan.

"There are limited options for people with PTSD," Miller says. "We asked whether we could identify something unique to the storage of traumatic memories to get at the heart of the problem."

About 10 percent of women and 4 percent of men will experience post-traumatic stress disorder at some point in their lives, putting them at risk for depression and drug addiction, with rates even higher in the military. An estimated 8 million people a year in the United States cope with the disorder. Sleep, thinking, relationships and jobs frequently suffer.

"The main medications used to treat PTSD are selective serotonin reuptake inhibitors, or SSRIs. They can help symptoms, but for many, they don't help enough," Miller says. "There's nothing available that targets the traumatic memories themselves."

In prior work, Miller has developed a potential drug that disrupts long-term emotional memories of methamphetamine use as a strategy for prevention of relapse in drug addiction. That success convinced her that it might also be possible to disrupt long-term emotional memories specific to PTSD to boost resilience.

Within our cells, microRNA molecules serve to regulate how our genes are expressed. More than 2,000 different types of microRNAs have been identified recently. Discoveries from Scripps Research and elsewhere have shown its possible to design drug molecules to regulate them as a way of targeting diseases once thought undruggable.

"We chose to focus on microRNAs because of their ability to titrate the expression of many molecules involved in memory, not just one, and we focused on microRNAs expressed specifically under conditions of stress susceptibility to avoid wiping out people's memories in general," Miller explains.

Her group worked first with stress-conditioned mice to identify microRNA unique to those who appeared permanently changed by their stress exposure. The mouse research revealed mir-135b-5p as a key differentiator between stressed and resilient mice. Next, they exposed mice to stress conditioning and then silenced mir-135b-5p. Those without the microRNA proved uncommonly resilient.

Working with brain tissue samples from the Harvard Medical School Department of Psychiatry, Miller's group found that the microRNA was also conserved from mouse to humans. Next, they identified a consortium in the Netherlands that had collected blood samples six months after Dutch military veterans had served in Afghanistan conflict zones for four-month tours. Some had been diagnosed with PTSD.

In the serum from the PTSD group, they likewise found selective elevation of mir-135b's "passenger" strand.

Looking ahead, Miller wants to explore how time course may affect response to treatment, and how gender differences may involve alternate traumatic memory storage mechanisms. The data from mice suggested a different mechanism was at work in the females, she says.

"I'm excited about the potential of this as a therapeutic target," Miller says. "The passenger strand may be a biomarker of responsivity to a mir-135-based therapeutic."

Prejudice among white people can lessen over time, according to new research from Rice University.

"'Who Cares?': Investigating Consistency in Expressions of Racial Apathy among Whites," appears in the journal Socius: Sociological Research for a Dynamic World. The study examines how some white people express racial prejudice - in the form of racial apathy - over time. The researchers also developed a new way to measure this type of prejudice.

Tony Brown, a professor of sociology at Rice and the study's lead author, focused on this topic because of changes in how prejudice is expressed; this field of study has moved away from reliance on blatant indicators of white racial prejudice and now focuses on subtle and colorblind indicators, such as racial apathy.

Brown said racial indifference is as insidious as blatant hostility because it absolves whites of responsibility for racism.

"In today's society it's more acceptable for whites to admit that they do not care about racial equality than for them to admit that they would not date or marry a person of a different race or vote for a black political candidate, or for them to say that blacks are unintelligent, lazy and prone to violence, or that blacks and whites should live in separate neighborhoods," he said.

For the study, Brown and his co-authors used three waves of panel data (2003, 2007-08 and 2013) from the National Study of Youth and Religion, a representative survey of 3,290 white youths between the ages of 13 and 17 during the first wave of the survey. The participants were interviewed about their personal views on racial equality and related issues.

Using their new measure (the question, "How much do you personally care or not about equality between different racial groups?"), the researchers examined the distribution of racial apathy over time. Forty-nine percent of individuals surveyed in 2003 said they cared "very much" about racial inequality, and this number grew to 56% in 2013. Sixteen percent of respondents said they "do not really care" about racial inequality in 2003, but this number dropped to just 10% in 2013. There were small drops (2% for each group) in the number of individuals who said they cared "somewhat" or "a little" about racial inequality.

Interestingly, 46% of individuals who said they "do not really care" about racial inequality in 2003 cared "very much" about racial inequality by 2013. This dramatic shift suggests white prejudice can lessen over time.

The researchers also found a correlation between prejudice and the grades people earn in school. Over time, individuals with better grades tended to report lower levels of racial apathy.

"These results are encouraging as they suggest that time and factors such as education may lessen feelings of racial apathy among some white people," Brown said. His future work will focus on explaining why some white people start to care more about racial inequality as they get older.

The paper was co-authored by Rice sociology graduate students Asia Bento, Quintin Gorman, Lydia Koku and Julian Culver. The research was partially funded by the Lilly Endowment.

Baltimore, Md -- About 1 in 10 pregnant women experience placenta abnormalities that lead to life-threatening preeclampsia (hypertension), preterm labor and fetal growth problems, but finding effective treatments to effectively prevent or reverse these conditions has so far been elusive.

A new finding from University of Maryland School of Medicine (UMSOM) researchers, published in the June issue of the journal Endocrinology, could have important implications for developing novel treatments to prevent placental abnormalities. The study, which involved female non-human primates, provided confirmatory evidence that elevated levels of the female hormone estrogen early in pregnancy leads to abnormalities in the uterine artery that lessens blood flow to the placenta, providing less nourishment to the fetus. Instead of adapting to the increased blood flow of pregnancy by becoming more pliant -- known as uterine artery remodeling -- the arteries remain rigid when estrogen levels are elevated, which impedes blood flow and oxygen delivery to the placenta and, in turn, to the fetus.

More importantly, the researchers demonstrated for the first time that the condition can be reversed by delivering a signal protein called vascular endothelial growth factor (VEGF) to the maternal side of the placenta, which is attached to the uterine lining; pregnant primates with elevated estrogen levels that were treated with this growth factor during the first trimester of pregnancy experienced an increase in uterine artery remodeling and were more likely to deliver normal weight babies compared to those who were not treated with VEGF.

"Our findings show that VEGF plays an important role in helping to promote proper blood flow to the placenta, which could help prevent pregnancy complications that occur with defective uterine artery remodeling," said Eugene D. Albrecht, PhD, a Professor of Obstetrics, Gynecology and Reproductive Sciences at UMSOM and lead investigator on the study. "If our exciting finding can be replicated in pregnant women, VEGF could have the potential for preventing preeclampsia and other problems associated with placenta abnormalities."

To conduct the study, Dr. Albrecht and his colleagues treated 17 pregnant female primates with daily estradiol (the female hormone estrogen) during the first several weeks of pregnancy to elevate their estrogen levels and suppress uterine artery remodeling. Six of those pregnant primates were also infused briefly via a peripheral vein in their arm with VEGF treatment four times during the first trimester of pregnancy; the treatment consisted of the gene for VEGF that was attached to tiny microbubbles that circulated throughout the bloodstream. During each infusion, the researchers directed a beam of sound waves delivered via a contrast-enhanced ultrasound transducer to the uterine arteries, which caused the microbubbles to burst. This freed the VEGF gene which could then bind to cell receptors in the placenta and uterine arteries, promoting a beneficial increase in uterine artery remodeling. (The microbubbles of VEGF that circulated elsewhere through the body were not activated, so VEGF would not have any unintended consequences on blood vessels other than in the uterus.)

Images of the uterine arteries revealed an increase in uterine artery remodeling in the primates that were treated with VEGF while those that received estrogen alone had a decrease in this remodeling. More importantly, the researchers found that blood flow through the placenta was reduced in those primates who were not treated with VEGF and that the body weight of the newborns was 10 percent lower on average.

VEGF is thought to increase uterine remodeling by increasing cell migration to artery walls where the cells do a renovation of sorts replacing smooth muscle cells and elastic fibers within the arteries to make them into less resistant to able to withstand a higher capacity of blood flow.

"This is the kind of cutting-edge science that defines our mission. This important new study provides vital evidence to explain one pathway that could lead to pregnancy-related complications, and we are eager to take the next step which is to replicate the research in pregnant women," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. and Akiko K. Bowers Distinguished Professor and Dean, University of Maryland School of Medicine.

Women who develop preeclampsia currently have few effective treatments beyond delivering the baby, which often must occur before the pregnancy has reached full term to reverse the sudden, dangerous rise in blood pressure. There are also few treatments to halt pre-term labor or treat fetal growth problems. These three conditions combined contribute to more than half of all medically induced deliveries before 35 weeks in the United States and are associated with disproportionately high rates of life-threatening complications and death in newborns.

Previous research has found an association between high estrogen levels, often resulting from fertility treatments, and the development of these placenta abnormalities in pregnant women, though other factors may also contribute including a family history and previous pregnancy complications involving the placenta.

Dr. Albrecht and his UMSOM colleagues who led the study have currently enrolled more than 100 pregnant patients in a new study where they are conducting 4-D ultrasound imaging to determine whether they can identify abnormalities in uterine artery remodeling early in human pregnancy. If that research has positive results, the researchers can then begin trials of VEGF treatments in pregnant women.

Five- and six-year-old boys and girls who are inattentive in kindergarten are more likely to report lower incomes than other children when they reach 33 to 35 years of age, a new Université de Montréal study has found.

On the other hand, the most "pro-social" boys (those who help others, are considerate and willing to participate in educational projects) are overwhelmingly headed for careers that pay more than the average, the researchers discovered.

"Over a 25-year career, the differences between the two groups can reach $77,000," said UdeM public-health professor Sylvana Côté, lead author of the study published this week in the Journal of American Medical Association (JAMA) Psychiatry.

"And all this has nothing to do with intelligence or IQ because extreme cases have been excluded from the sampling," she added.

"The differences are significant between the groups studied, but the precise reasons for these disparities are still difficult to identify," said Côté, who specializes in child development.

Problems of inattention more often lead to kids dropping out of school or having trouble adjusting as they enter the labour market. On the other hand, the researchers found, "prosocial" children are on a trajectory that leads to better-paying jobs.

Three decades of data

Spanning nearly three decades, the study used data from the Research Unit on Children's Psychosocial Maladjustment, and involved more than 3,000 kids who were in kindergarten in 1985. Behaviours were evaluated over time through questionnaires.

This is the first time that "pro-sociality" has been studied in a survey of this kind - and its positive effect came as a surprise to the team.

"We expected to find differences between boys and girls and we did find some important ones," said Côté. "We expected hyperactivity to be the most important variable, but in fact it turned out to be less important than simple lack of attention."

Differences were evident when data was crunched for in 2015, a year when the grow-ups were in the prime of their working lives and when the wage gaps between individuals were stark.

"Our study," the authors write, "shows that childhood inattention is associated with a wide range of long-term adverse outcomes, including lower earnings over the course of a career."

They add that early follow-up and care for very inattentive children and boys who rarely express prosocial behaviours "could result in long-term socio-economic benefits for individuals and society."

A team effort

The study was an international team effort. UdeM postdoctoral fellow Francis Vergunst is first author, aided by professors Richard E Tremblay and Frank Vitaro, academics in the U.S. (Daniel Nagin) and France (Yann Algan, Elizabeth Beasley and Cedric Galera), and Statistics Canada's Jungwee Park.

The research was conducted at the Centre interuniversitaire québécois de statistiques sociales (CIQSS), which provides researchers with access to detailed data from Statistics Canada and Institut de la statistique du Québec surveys. Based on tax returns, the data is coded to prevent the identification of subjects.

For three years, Sylvana Côté and her collaborators worked to collect the data and link them to the psychosocial observations of the study subjects. "All this research is ultimately aimed at improving interventions for young people in order to make them as optimal as possible," said Côté.

An unexpected result: 30% less income for women

In general, three decades after kindergarten, women earn only 70 per cent of what men earn, according to the UdeM study in JAMA of 3,040 five- and six-year-olds who entered the Quebec school system in 1985.

"This result underlines that the origins of gender disparities in childhood are poorly understood and deserve to be studied," said lead author Sylvana Côté, a child development specialist at UdeM.

With the help of economists and statisticians, Côté said she will try to find answers to the questions raised by this collateral result of her longitudinal research on the effects of preschool behaviour.

"These girls are now 35 to 40 years old," she said. "They are as educated as boys and have similar experiences. Are there any individual, family or school factors in childhood or adolescence that would explain the income gap? That's what we'll try to find out."

Palo Alto, CA--What factors govern algae's success as "tenants" of their coral hosts both under optimal conditions and when oceanic temperatures rise? A Victoria University of Wellington-led team of experts that includes Carnegie's Arthur Grossman investigates this question.

Corals are marine invertebrates that build large exoskeletons from which colorful reefs are constructed. But this reef-building is only possible because of a mutually beneficial relationship between the coral and various species of single-celled algae called dinoflagellates that live inside the cells of coral polyps.

These algae are photosynthetic, which means that like plants they can convert the Sun's energy into chemical energy in the form of food. Many of the photosynthetically derived nutrients synthesized by an alga serve as food for its coral host, while the host in turn provides the alga with essential inorganic nutrients, including carbon dioxide, nitrogen in the form of ammonium, and phosphate. However, ocean warming due to climate change is causing many corals to lose their native algal tenants--along with the nutrients that they provide--a phenomenon called bleaching. If the bleached coral is not recolonized with new algal tenants, it can die.

Some species of the dinoflagellate algae form these symbiotic relationships with multiple types of coral, others are more specific.

"We're interested in understanding the cellular processes that maintain those preferential relationships," Grossman said. "We also want to know if it's possible that more heat tolerant, non-preferred algae could revive bleached coral communities even if the relationship is less efficient."

Other organisms such as sea anemones are part of the same phylum as coral, called cnidaria; they also host algae but are easier to study. In this paper--published by The ISME Journal--the researchers analyzed the differences in cellular function that occurred when a type of anemone called Exaiptasia pallida was populated by two different genera of dinoflagellate algae--one native and highly susceptible to thermal bleaching and the other, which is non-native but more heat-resistant.

"In this study we hoped to elucidate proteins that function to improve nutrient exchange between the anemone and its native algae and why the anemone's success is compromised when it hosts the non-native heat resistant algae," Grossman said.

The team found that anemones colonized by native algae expressed elevated levels of proteins associated with the metabolism of organic nitrogen and lipids--nutrients that can be efficiently synthesized as a consequence of the algae's photosynthetic activity. These anemones also synthesized a protein called NPC2-d which is thought to be key to cnidarian's ability to take up the algae and recognize it as a symbiotic partner.

In contrast, anemones with the non-native tenant expressed proteins associated with stress, which likely reflects less optimal integration of the metabolisms of the two organisms.

"Our findings open doors to future studies to identify key proteins and cellular mechanisms involved in maintaining a robust relationship between the alga and its cnidarian host and the ways in which the metabolism of the organisms are integrated," Grossman concluded.

Chestnut Hill, Mass. (6/19/19) - Nearly two decades removed from a brutal civil war that made them both captives and combatants, many of the former child soldiers of Sierra Leone have gradually earned greater acceptance from families and communities as they try to overcome their childhood trauma, according to a sweeping new report on their adult lives from a team led by Boston College researchers.

Former child soldiers experience mental health problems as a result of their experiences, but earning acceptance from families and communities shapes the lives of these men and women and shows promise to help them to continue to improve emotionally and socially, according to the groundbreaking study, published in the online edition of Journal of the American Academy of Child and Adolescent Psychiatry.

It may take a greater focus on family- and community-based approaches to help former child soldiers achieve social reintegration, according to the co-authors, a group of professors and researchers from Boston College, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Harvard's T. H. Chan School of Public Health, and Child Trends of Bethesda, Md.

"Not only were child soldiers exposed to horrors during the war, but when they returned to their families and communities stigma was one of the biggest barriers to overcome. We set out to study the effects of the post-war environment on these already-vulnerable youth," said lead author and Boston College School of Social Work Salem Professor in Global Practice Theresa Betancourt, one of the project's founding researchers

During the 11-year civil war, several warring factions abducted children and forced their involvement in armed groups. An estimated 15,000 to 22,000 boys and girls of all ages were subject to repeat sexual violence, forced use of alcohol and drugs, hard physical labor, and acts of violence until the war ended in 2002.

The Longitudinal Study of War-Affected Youth interviewed 500 former child soldiers beginning in 2002 and periodically through 2016-2017, the latest survey of these individuals.

The grim statistics of their lives under the control of rival warlords recalls the grisly nature of the conflict in Sierra Leone. The average age of the respondents is now 28. More than a quarter of them reported they had killed or injured others while conscripted. Nearly half of the women surveyed and five percent of the men reported having been raped. Thirty-two percent reported the death of a parent.

"Sierra Leone's child soldiers experienced violence and loss on a scale that's hard to comprehend," said study co-author Stephen Gilman of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Nearly half the respondents detailed symptoms of anxiety and depression, with 28 percent suffering from post-traumatic stress disorder, according to the recent report, titled "Stigma and Acceptance of Sierra Leone's Child Soldiers: A Prospective Longitudinal Study of Adult Mental Health and Social Functioning."

A deeper examination of the respondents' lives - particularly the stigma they are subject to and the level of acceptance by family and community - led to the classification of three groups:

The Socially Protected group, nearly two-thirds of the respondents, reported they were not heavily stigmatized for their war involvement and had high levels of acceptance from their families and communities. This group reported largely that they had lower levels of exposure to wartime violence.

The Improving Social Integration group included respondents who in 2002 reported high levels of stigmatization and low rates of acceptance. This group, largely female and more likely to have been raped, have since reported a decrease in stigma and increase in acceptance by families and communities.

The Socially Vulnerable group - roughly 10 percent of the respondents - report adverse mental health outcomes and only slight improvements from 2002, when they were highly stigmatized and had low family and community acceptance. This group is largely male, spent more time in fighting forces and were more likely to have killed or injured others during the war.

Those in the Improving Social Integration group made gains, though they reported problems such as getting in trouble with local police. However, members of the socially vulnerable group were about twice as likely as those in the socially protected group to experience high levels of anxiety and depression. They were three times more likely to have attempted suicide and over four times more likely to have been in trouble with the police.

The authors concluded that efforts to address family and community relationships with particular attention to improving social supports and reducing stigma remain critical ingredients of interventions to help former child soldiers adapt to post-conflict life.

"There is healing power in the relationships young people build within their families and communities," said Betancourt, who directs the Research Program on Children and Adversity at BC. "What these latest findings show is that just as much attention should be paid to family and community relationships as to the traumatic events of their past. Efforts to alleviate mental health problems and improve life outcomes for former child soldier need to focus much more on family and community relationships."

Participants in the study have been interviewed four times - in 2002, 2004, 2008, and 2016 to 2017 - about their involvement with armed groups, exposure to violence in the war, and about their family and community relationships after the war. Interviewers also asked questions assessing their mental health status and their psychological adjustment at multiple time points.

"Conducting a study like this over so many years in Sierra Leone is a real challenge," said co-author and Research Program on Children and Adversity statistician Robert T. Brennan. "Addresses are approximate, birthdays, even ages, are often unknown, and natural disasters displace whole communities. We even had to postpone data collection due to the Ebola outbreak of 2014 to 2015."

"Because this study follows a single cohort of former child soldiers - some as young as 10 years old - into young adulthood, it is certain to be a landmark in the study of the exploitation of children by armed groups," said Boston College School of Social Work Dean Gautam N. Yadama.

Andrés Martínez strode briskly on the treadmill, staring straight ahead and counting backwards by seven from 898, a trick to keep his brain from anticipating the literal stumbling block heading his way: a compact 35 pounds of steel specifically designed to make him fall.

Special goggles kept him from looking down. Arrows on an eye-level screen kept him from walking off the sides. A harness attached to a ceiling beam kept him safe. Sure enough, when a computer program released the steel block, it glided onto the treadmill, and the Vanderbilt University PhD student struggled to stay on his feet.

That automatic stumble response, so natural for most people, is virtually impossible for those who use prosthetic legs, simply because even state-of-the-art prosthetics cannot adapt to stumbling. Patients with above-the-knee amputations are far more likely to fall than typical counterparts in their age group.

The first step a Vanderbilt team took in addressing that challenge in lower-body prosthetics was coming to understand the way people with two legs catch themselves, accomplished by covering test subjects with motion-capturing sensors. It also required tripping them over and over - 190 times, to be exact -- for a study published this month in the Journal of NeuroEngineering and Rehabilitation. But because humans are so mentally geared to resist stumbling, a team of Vanderbilt mechanical engineers first had to design the stumbling device described above.

"Not only did our treadmill device have to trip them, it had to trip them at specific points in their gait," said Shane King, a PhD student and lead author on the paper. "People stumble differently depending on when their foot hits a barrier. The device also had to overcome their fear of falling, so they couldn't see or feel when the block was coming."

In addition to protecting test subjects, the harness included a scale. If a subject put 50 percent or more of their weight on it, that counted as a fall. The team's design for the machine and outcomes of their tests are available for other labs to use in the open-source journal.

Michael Goldfarb, H. Fort Flowers Professor of Mechanical Engineering and the principal investigator on the study, said designing the stumble device and measuring outcomes was only the first of three parts.

"So now we understand what the stumble reflex should look like," he said. "The next phase is to take that information and program it into computer-controlled prosthetic legs. After that, we will safely stumble amputees wearing both commercially available prosthetics and the ones we've designed with these reflexes and learn whether ours can prevent more falls."

Vocabulary tests for individuals with the severest forms of autism spectrum disorder, or ASD, are notoriously inaccurate. They commonly ask the test-taker to point to an illustration after hearing a spoken word, measuring the ability to understand and perform a task as much as word knowledge.

The implications are significant. Poor assessments result not only in teaching strategies that are ineffective but also make researchers wary, leading to a shortage of research on individuals with Level 3 ASD, the diagnosis given to the most severe forms of autism, that could help improve their quality of life.

That's according to Emily Coderre, lead author of a new study in the journal Cognitive and Behavioral Neurology and a faculty member in the University of Vermont's Department of Communication Science and Disorders.

In the new study, Coderre and colleagues at Johns Hopkins Medicine demonstrate that assessment tools capturing implicit signs of word knowledge like eye movement among those with Level 3 ASD - tools that have rarely been used with this group - offer the potential to be more accurate than traditional behavioral assessments, closely matching the reports of parents and caregivers, the current "gold standard" for determining an individual's vocabulary knowledge.

"Children and adults with severe ASD often score much lower than they should on traditional language assessments," Coderre said. "They may not understand the instructions or be unable to point to a picture after hearing the spoken word. Or they may be frightened by the equipment or simply not care to participate. The new study points the way toward a much better approach."

Three implicit measures of word knowledge

To assess vocabulary knowledge among five adults with Level 3 ASD, researchers in the study used what are called implicit measures of word knowledge.

In one test researchers used a technique called eye movement monitoring. After hearing a spoken word, which matched one of four illustrations on a computer screen, the researchers tracked the subjects' eye movements. If their eyes quickly chose the matching visual and stayed with it, that signaled knowledge of the word. If the eyes flitted from one object to the next, it demonstrated the word was probably not known.

In a second test called pupillary dilation, subjects again heard a spoken word and were shown four visuals. If the pupils dilated, that signaled cognitive effort, and the probability that the word was not known. If pupils did not dilate, that likely demonstrated knowledge of the word.

In a third test, researchers used electroencephalography to measure brain activity in the research subjects. Subjects heard a word and were shown an image that either matched or did not match it. Earlier research has shown there are typical brain patterns for congruent and incongruent pairs of words and images, enabling the researchers to infer whether the word was known based on these electrical signatures.

The three measures had varying degrees of accuracy with each of the five research subjects. Although the researchers concluded that these implicit measures show promise in providing estimates of vocabulary knowledge, this variability suggests that these assessments should be tailored to each individual.

An earlier study by the research team offered further validation of the research findings. That study found that the three implicit measures were highly accurate in assessing word knowledge among a group of adults who did not have ASD.

Better interventions, more knowledge

Given the small research sample, the research findings are preliminary. But their potential implications are significant, Coderre said.

Implicit measures of vocabulary could result in more effective interventions that are tailored to the true language knowledge of the individual.

"Language is often one of the areas where individuals with autism struggle, especially at the more severe end of the spectrum, where a large percentage have little to no functional language," Coderre said. "Anything we can do to improve their language outcomes will improve their quality of life."

The new tools could also result in more research into those with severe ASD, she said, not only in language acquisition but in other areas of cognition.

Nonverbal intelligence testing often relies on visual clues, for instance, she said. Subjects might be shown an image of a puzzle with a missing piece and be asked to find the piece among several options, a task well suited to the EM and PD testing.

"These techniques could very well be extended to other domains," Coderre said.

That could help address a challenge in the field - the huge lack of literature on individuals with Level 3 ASD.

"There's so much focus on the milder end of the spectrum, the people who are more functionally verbal, that people on the more severe end of the spectrum tend to be overlooked," Coderre said.

"With measures like these, we can do not only more interventions-based research, but also work with this population in general, so we can better understand how their strengths and weaknesses are similar to or different from other individuals on the spectrum. The more understanding we have, the more help we can offer."