Culture

Scientists have developed a personalized platform tailored to patients' specific cancer mutations named TARDIS, which was able to accurately detect circulating tumor DNA (ctDNA) and signs of residual disease in 33 women with breast cancer. Their technology demonstrated a hundredfold improvement in sensitivity compared to previous approaches. Although more testing is needed, the assay could one day be used to help monitor how patients respond to chemotherapy and to identify recurrences of tumors earlier on. In recent years, researchers have developed an array of techniques to detect or monitor cancers by examining ctDNA - DNA shed from the tumor site that circulates in the blood. However, ctDNA is often present in much lower amounts compared to circulating DNA from non-tumor cells, making it difficult to detect, especially in patients who have already received chemotherapy. This obstacle has impeded the creation of a platform sensitive enough to detect signs of recurring disease - a chief concern in many cancer patients. To solve this issue, Bradon McDonald and colleagues created TARDIS, a sequencing platform that analyzes patient-specific mutations from limited sample sizes. Their assay analyzes an amount of DNA equivalent to a single tube of blood and can simultaneously study eight to 16 known mutations. TARDIS successfully detected ctDNA in plasma samples from 33 patients with breast cancer before they started treatment, and revealed the patients had lower concentrations of ctDNA after treatment was completed. Furthermore, patients who responded the best to chemotherapy displayed a 96% decrease in ctDNA abundance, while patients with residual disease showed a 77% decrease - indicating the platform could guide the personalized management of patients at risk of cancer recurrence. In a related video, the researchers say that their findings must be validated in larger trials before TARDIS can be employed in the clinic. Next steps also include scaling up the platform for use in hundreds of patients.

Forgotten immune cells protective in mouse model of multiple sclerosis, Stanford study finds

A seldom-studied class of immune cells may reduce the friendly fire that drives autoimmune disease, according to a new study by researchers at the Stanford University School of Medicine. Stimulating these protective cells could lead to new therapies for diseases in which the immune system attacks the body's own tissues, such as multiple sclerosis and celiac disease.

In the study, to be published Aug. 7 in Nature, researchers tracked immune cells in the blood of mice with a disease akin to multiple sclerosis. They discovered a rise in CD8 T cells, typically known for killing infected or cancerous cells. To their surprise, injecting mice with peptides recognized by these CD8 T cells reduced disease severity and killed disease-causing immune cells.

While the bulk of the study was done in mice, the researchers also showed that one of their central findings -- an increase in CD8 T cells derived from single cells -- held true in cells from people with multiple sclerosis.

The findings suggest that inflammatory and suppressive immune cells balance each other like children on a seesaw. Selectively activating suppressive CD8 T cells during autoimmune disease may help restore that balance, said Mark Davis, PhD, professor of microbiology and immunology and the study's senior author.

"We absolutely think that something like this is happening in human autoimmune diseases. It represents a mechanism that nobody's really appreciated. There's this whole subset of CD8 T cells that has a suppressive function," said Davis, who holds the Burt and Marion Avery Family Professorship and is also a Howard Hughes Medical Institute investigator. "If we could mobilize those cells to function more effectively in patients with autoimmunity, then we'd have a novel treatment for diseases like multiple sclerosis."

Attack of the T cell clones

In most cases, researchers don't know what molecules trigger autoimmune diseases, which affect 23.5 million Americans, according to the National Institutes of Health.

Multiple sclerosis is no exception. But scientists can trigger a similar disease in mice by injecting them with a small chunk, or peptide, of a protein called myelin oligodendrocyte glycoprotein, or MOG. Mice with the disease, known as experimental autoimmune encephalomyelitis, develop paralysis just like patients with multiple sclerosis.

The researchers used this mouse model of the disease to investigate what different immune cells were doing during autoimmunity. They tracked the abundance of various classes of immune cells in mice injected with MOG.

They found that the number of T cells, which act like generals in directing the overall scale and strategy behind an immune response, rose and fell like waves. DNA sequencing showed that those waves were each made of groups of identical cells -- an important clue.

"When T cells encounter a pathogen, or antigen, single cells that recognize some part of the pathogen divide and produce many copies of themselves," said research associate Naresha Saligrama, PhD, the study's lead author. "This suggested that a specific population of cells were responding."

But what were these T cells responding to? Saligrama first tested the most obvious suspect: MOG. He exposed the cells to 350 peptides derived from MOG. But while MOG caused some T cells to proliferate, there was a group of CD8 T cells that didn't respond to any of the peptides.

So instead, the researchers cast a much wider net: They tested roughly 5 billion peptides. They used a molecular technique known as yeast display to generate an array of peptides attached to individual yeast cells.

"We are crowdsourcing the T cells. We're asking the T cells, as the disease is progressing, what they are interested in," Davis said. "We're not trying to guess or hypothesize what they are recognizing."

Resurrecting the Titanic

The researchers found two peptides recognized by CD8 T cells involved in the disease. To understand the role of these peptides, they injected them into mice before, after or alongside MOG. Since CD8 T cells are mainly known for killing cancerous and infected cells, the scientists expected that activating these cells would worsen disease.

They were wrong. Activating the CD8 T cells by administering the two peptides consistently reduced or prevented disease in the mice. It was the exact opposite of what they'd expected.

The startling finding forced the researchers to unearth an idea first proposed in the 1970s: that some CD8 T cells are immunosuppressive. After a flurry of initial interest and promising papers, faith in suppressor CD8 T cells sunk once speculation outpaced the actual data.

"Suppressor CD8 T cells did for immunology what the Titanic did for the cruise industry," Davis said.

Davis and his colleagues found that these peptide-activated CD8 T cells killed disease-causing T cells by punching holes in their cell membrane when grown together in a dish. The CD8 T cells were also coated with surface proteins associated with immunosuppression -- yet another clue that these cells were in fact suppressor CD8 T cells.

To determine whether their mouse observations held up in humans, the researchers isolated CD8 T cells from the blood of people with multiple sclerosis and healthy donors. They found that people with the disease tended to have large populations of identical CD8 T cells -- just like in mice with the analogous disease. It's a sign that CD8 T cells in multiple sclerosis are homing in on something, and Davis' team is now working to determine what these cells are recognizing and if some of them are suppressive.

The researchers also plan to test if suppressor CD8 T cells are involved in other autoimmune diseases. Previous findings from the Davis lab suggest that a similar mechanism may be at work in celiac disease. These efforts have the potential to shed new light on how autoimmune diseases work and to uncover new therapeutic targets.

"Crowdsourcing T cells is a fundamentally different way to look at disease," Davis said. "This project shows not only the power of this approach but the power to discover new mechanisms."

Astronomers used the combined power of multiple astronomical observatories around the world and in space to discover a treasure-trove of previously unknown ancient massive galaxies. This is the first multiple discovery of its kind and such an abundance of this type of galaxy defies current models of the universe. These galaxies are also intimately connected with supermassive black holes and the distribution of dark matter.

The Hubble Space Telescope gave us unprecedented access to the previously unseen universe, but even it is blind to some of the most fundamental pieces of the cosmic puzzle. Astronomers from the Institute of Astronomy at the University of Tokyo wanted to see some things they long suspected may be out there but which Hubble could not show them. Newer generations of astronomical observatories have finally revealed what they sought.

"This is the first time that such a large population of massive galaxies was confirmed during the first 2 billion years of the 13.7-billion-year life of the universe. These were previously invisible to us," said researcher Tao Wang. "This finding contravenes current models for that period of cosmic evolution and will help to add some details, which have been missing until now."

But how can something as big as a galaxy be invisible to begin with?

"The light from these galaxies is very faint with long wavelengths invisible to our eyes and undetectable by Hubble," explained Professor Kotaro Kohno. "So we turned to the Atacama Large Millimeter/submillimeter Array (ALMA), which is ideal for viewing these kinds of things. I have a long history with that facility and so knew it would deliver good results."

Even though these galaxies were the largest of their time, the light from them is not only weak but also stretched due to their immense distance. As the universe expands, light passing through becomes stretched, so visible light becomes longer, eventually becoming infrared. The amount of stretching allows astronomers to calculate how far away something is, which also tells you how long ago the light you're seeing was emitted from the thing in question.

"It was tough to convince our peers these galaxies were as old as we suspected them to be. Our initial suspicions about their existence came from the Spitzer Space Telescope's infrared data," continued Wang. "But ALMA has sharp eyes and revealed details at submillimeter wavelengths, the best wavelength to peer through dust present in the early universe. Even so, it took further data from the imaginatively named Very Large Telescope in Chile to really prove we were seeing ancient massive galaxies where none had been seen before."

Another reason these galaxies appear so weak is because larger galaxies, even in the present day, tend to be shrouded in dust, which obscures them more than their smaller galactic siblings.

And what does the discovery of these massive galaxies imply?

"The more massive a galaxy, the more massive the supermassive black hole at its heart. So the study of these galaxies and their evolution will tell us more about the evolution of supermassive black holes, too," said Kohno. "Massive galaxies are also intimately connected with the distribution of invisible dark matter. This plays a role in shaping the structure and distribution of galaxies. Theoretical researchers will need to update their theories now."

What's also interesting is how these 39 galaxies are different from our own. If our solar system were inside one of them and you were to look up at the sky on a clear night, you would see something quite different to the familiar pattern of the Milky Way.

"For one thing, the night sky would appear far more majestic. The greater density of stars means there would be many more stars close by appearing larger and brighter," explained Wang. "But conversely, the large amount of dust means farther-away stars would be far less visible, so the background to these bright close stars might be a vast dark void."

As this is the first time such a population of galaxies has been discovered, the implications of their study are only now being realized. There may be many surprises yet to come.

"These gargantuan galaxies are invisible in optical wavelengths so it's extremely hard to do spectroscopy, a way to investigate stellar populations and chemical composition of galaxies. ALMA is not good at this and we need something more," concluded Wang. "I'm eager for upcoming observatories like the space-based James Webb Space Telescope to show us what these primordial beasts are really made of."

Munching on low-fat potato chips might reduce the guilt compared with full-fat versions, but many people don't find the texture as appealing. Now, researchers have developed a technique to analyze potato chips' physical characteristics from simulated first bite to swallow, which they say could be used to help formulate a tastier low-fat snack. They report their results in the Journal of Agricultural and Food Chemistry.

Cutting fat in potato chips usually involves reducing the vegetable oil content. However, the oil helps give the product its characteristic crunch, taste and mouthfeel. When food scientists formulate a new low-fat chip, they often rely on trained sensory panelists to tell them how well the new snack simulates the full-fat version. This process can be expensive, time-consuming and often subjective, since perceptions can vary based on factors like a person's saliva flow rate and composition. While at PepsiCo, Stefan Baier -- now at Motif Ingredients -- and Jason Stokes' team at the University of Queensland  wanted to develop a more objective method to analyze the physical characteristics of a potato chip at four stages of simulated eating: the first bite, when the chip is taken from the package and broken by the teeth; comminution, when the chip particles are broken down further and wet by saliva; bolus formation, when the small, softened particles begin to clump as enzymes in saliva digest the starches; and swallow, when the clumped mass moves to the rear of the mouth and is finally swallowed.

To develop their method, called in vitro oral processing, the researchers used different instruments to measure the physical characteristics of chips with various oil contents at each of the four stages. For example, for the "first bite" stage, they conducted mechanical testing to measure the force required to break the chips, and for bolus formation, they measured the hydration rate of particles in buffer as the fragments became a soft solid. The researchers used the results to design a lower-fat chip coated in a thin layer of seasoning oil, which contained a small amount of a food emulsifier. The seasoning oil made the low-fat chip more closely resemble the greasiness of a full-fat one in tests with sensory panelists, but it only added 0.5% more oil to the product. Food scientists could use the new technique to link physical measurements with sensory perceptions, the researchers say.

Mistrust of health care providers, fueled by painful experiences with racism, makes African American men more likely to delay routine screenings and doctor's appointments, according to a new study in the journal Behavioral Medicine by the Health Disparities Institute (HDI) at UConn Health, with potentially serious implications for their overall health.

"Medical mistrust is significantly contributing to delays in African American men utilizing the health care system," says Dr. Wizdom Powell, the study's lead author, who is HDI director and associate professor in the Department of Psychiatry at UConn School of Medicine.

The new study reports that "medical mistrust" - defined as a suspicion or lack of trust in medical organizations - is associated with delays in African American men's routine health visits, blood pressure, and cholesterol screenings. It also found that men who report experiencing frequent everyday racism had higher odds of delaying screenings and routine health care visits. Also, those who perceived racism in health care had more medical mistrust with significantly reduced rates of preventive health care utilization.

"We must address medical mistrust and racism in and outside of health care institutions to increase lifesaving preventive health screenings among the high risk population of African American men," says Powell.

The research study analyzed associations between medical mistrust, perceived racism in health care, everyday racism, and preventive health screening delays. The cross-sectional data of 610 African American men aged 20 years and older was pulled from the African American Men's Health and Social Life study, with the majority of participants surveyed recruited from barbershops in Michigan, Georgia, California, and North Carolina, along with some from academic institutional events between 2003-2009.

For many African American men, that mistrust is rooted in personal experiences with prejudice and discrimination.

"Experience with racism in everyday life also appears to chip away at African American men's health care system trust and utilization," Powell says. "Thus, to improve African American men's health and life expectancy, we must also find ways to dismantle structural racism, as doing so is essential to eliminating long-standing health disparities."

While men, no matter their race, are less likely than women to pursue timely medical care, African American men's utilization patterns are even more delayed. Historically, African American men delay preventive health care more often than their white male counterparts, while also reporting higher levels of medical mistrust.

This is especially concerning because African American men's life expectancy at birth is already the shortest of all demographics in the U.S. African American men are at high risk for several conditions including cardiovascular disease, heart attack, and stroke. High blood pressure affects African-American men at a higher rate than any other demographic, along with disproportionate rates of obesity and diabetes. Blood pressure, cholesterol, and other routine health screenings can catch these conditions early enough to make treatment effective, but without that early intervention, the risk of heart attack and stroke increases dramatically.

According to Powell, this new study is one of only a few investigations into the role that medical mistrust and racism play in the likelihood of African American men seeking out routine preventive health screenings.

"Our findings underscore that delays in preventive health screenings are not just due to lack of health insurance and access to health care," says Powell. "Medical mistrust is a big factor deterring African American men from seeking care."

CHAMPAIGN, Ill. -- People who are the most optimistic tend to be better sleepers, a study of young and middle-aged adults found.

More than 3,500 people ages 32-51 were included in the study sample. The participants included people in Birmingham, Alabama; Oakland, California; Chicago; and Minneapolis.

The research was led by Rosalba Hernandez, a professor of social work at the University of Illinois.

"Results from this study revealed significant associations between optimism and various characteristics of self-reported sleep after adjusting for a wide array of variables, including socio-demographic characteristics, health conditions and depressive symptoms," Hernandez said.

Participants' levels of optimism were measured using a 10-item survey, which asked them to rate on a five-point scale how much they agreed with positive statements such as "I'm always optimistic about my future" and with negatively worded sentences such as "I hardly expect things to go my way."

Scores on the survey ranged from six (least optimistic) to 30 (most optimistic).

Participants reported on their sleep twice, five years apart, rating their overall sleep quality and duration during the prior month. The survey also assessed their symptoms of insomnia, difficulty falling asleep and the number of hours of actual sleep they obtained each night.

A subset of the participants was part of an ancillary sleep study based in Chicago and wore activity monitors for three consecutive days - including two weeknights and one weekend night. Participants wore the monitors on two occasions a year apart.

The monitors collected data on their sleep duration, percent of time asleep and restlessness while sleeping.

Hernandez and her co-authors found that with each standard deviation increase - the typical distance across data points - in participants' optimism score they had 78% higher odds of reporting very good sleep quality.

Likewise, individuals with greater levels of optimism were more likely to report that they got adequate sleep, slumbering six to nine hours nightly. And they were 74% more likely to have no symptoms of insomnia and reported less daytime sleepiness.

According to a 2016 report by the Centers for Disease Control and Prevention, about 1 in 3 U.S. adults fails to get adequate sleep, escalating their risks of many chronic diseases.

"The lack of healthy sleep is a public health concern, as poor sleep quality is associated with multiple health problems, including higher risks of obesity, hypertension and all-cause mortality," Hernandez said. "Dispositional optimism - the belief that positive things will occur in the future - has emerged as a psychological asset of particular salience for disease-free survival and superior health."

Although a significant and positive association was found between optimism and better-quality sleep, Hernandez suggested that the findings should be interpreted cautiously.

While the scientists aren't sure of the exact mechanism through which optimism influences sleep patterns, they hypothesize that positivity may buffer the effects of stress by promoting adaptive coping, which enables optimists to rest peacefully.

"Optimists are more likely to engage in active problem-focused coping and to interpret stressful events in more positive ways, reducing worry and ruminative thoughts when they're falling asleep and throughout their sleep cycle," Hernandez said.

The findings, published recently in the journal Behavioral Medicine, bolster those of a prior study, in which Hernandez and her co-authors found that optimists ages 45-84 were twice as likely to have ideal heart health.

Kiarri N. Kershaw, Juned Siddique, Honghan Ning and Donald M. Lloyd-Jones, all of Northwestern University; Julia K. Boehm of Chapman University; Laura D. Kubzansky of Harvard University; and Ana Diez-Roux of Drexel University co-wrote that study. That paper was published in the journal Health Behavior and Policy Review in 2015.

The sample for the current study was drawn from the Coronary Artery Risk Development in Young Adults study, which explored the development and progression of cardiovascular disease risk factors in a U.S. sample of non-Hispanic white and African American adults.

- Nearly 1 in 5 people with migraine use opioids to treat their headaches, up from 16 percent in 2009.

- People who experienced more frequent headaches were even more likely to use opioids to treat migraine, with more than half of them taking opioids at least one time to treat migraine.

- Clinical guidelines discourage the use of opioids for treatment of migraine symptoms, except in rare cases.

BOSTON - An increasing number of Americans are using opioids to treat their migraine headaches, despite the fact that opioids are not the recommended first-line therapy for migraine in most cases. That's according to the ObserVational Survey of the Epidemiology, tReatment and Care Of MigrainE (OVERCOME) study, a web-based patient survey of people living with migraine. Migraine care specialist Sait Ashina, MD, a neurologist and Director of the Comprehensive Headache Center at the Arnold-Warfield Pain Center at Beth Israel Deaconess Medical Center (BIDMC), presented the survey findings at the 61st annual meeting of the American Headache Society.

"These data show that, despite the known potential risks of using opioids for migraine, far too many continue to do so," said Ashina, who is an Assistant Professor in the Department of Neurology and Department of Anesthesia, Critical Care and Pain Medicine BIDMC and Harvard Medical School. "Against the backdrop of the U.S. opioid epidemic, it's concerning that people may be using these drugs in place of conventional therapies proven to be safer and more effective for migraine."

A prospective, web-based patient survey designed to follow two U.S. population samples of 20,000 people with migraine for two years, the OVERCOME study began enrollment in 2018, with a second population sample slated to begin enrollment in 2020. Analysis of data from the first group showed that 19 percent of people with migraine were currently using opioids specifically to treat migraine -- up from the 16 percent reported in 2009 in the American Migraine Prevalence and Prevention Study. Moreover, nearly a quarter of people who reported having four or more migraine headaches per month were currently using opioids to treat their pain, and more than half of these respondents reported taking opioids at least once to treat a migraine headache.

"OVERCOME showed that, overall, opioids are being used in place of medicines that are approved and indicated to treat migraine - particularly among those who experience migraine headaches more frequently," said Ashina. "Patients and doctors should work together to develop a personalized treatment plan tailored to address patients' particular health concerns and needs."

Migraine is a disabling neurological disease afflicting more than 37 million Americans, a burden disproportionately carried by women. In addition to severe headache pain, migraine symptoms vary from person to person - and from migraine episode to episode - but may include nausea and vomiting, extreme sensitivity to light, sound, smells and sensations, fatigue, and changes in mood. Migraine attacks can be brought on by specific triggers such as foods, stressors, hormones, or nothing at all, and can last for hours or days at a time.

Clinical guidelines from the American Headache Society encourage the use of triptans, a class of drugs introduced in the 1990s that stop about 75 percent of headaches within an hour and half, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen as first-line treatment for migraine headaches in most cases. The use of opioids as treatment for migraine headaches is typically reserved for patients in whom the use of triptans or NSAIDS is contraindicated.

Scandal gone viral has toppled many a leader, and new research shows it may have saved some too.

News and social media seem to thrive on sensationalizing scandal, and prominent CEOs, politicians, world leaders and sports stars often are forced to step down as a result. However, a new study from the University of Notre Dame introduces the role of the "severity gap," showing that when media or public perceptions of a scandal outpace its actual severity, strong-performing leaders are more likely to keep their jobs.

"How the severity gap influences the effect of top actor performance on outcomes following a violation" is forthcoming in the Strategic Management Journal from John Busenbark, assistant professor of management in Notre Dame's Mendoza College of Business.

Busenbark, along with co-authors Nathan Marshall, University of Colorado; Brian Miller, Indiana University; and Michael Pfarrer, University of Georgia, studied the performance, dismissal and labor market outcomes of NCAA Division I football and basketball head coaches in the wake of NCAA violations. They used rigorous and multiple econometric techniques to test ideas and reinforce findings.

"Our central finding is that organizations are less likely to dismiss stronger-performing leaders when there is a high severity gap, and this is because internal stakeholders want to protect their organization and its central figures from what they perceive as undue scrutiny," Busenbark says. "Weaker-performing leaders, however, are apt to get dismissed following a scandal with a larger severity gap. We argue this is because the excess drama from a large severity gap provides insiders with a perfect opportunity to scapegoat leaders they do not perceive as integral to the organization."

As it relates to the corporate world, the research is the first to demonstrate that there is often a disconnect between the perceived and actual severity of a scandal. Conventional logic would suggest that strong-performing managers would likely get dismissed after a negatively perceived event because insiders, whether other managers or a board of directors, want to distance themselves from a high-profile manager disliked by outsiders. However, the study reveals the opposite.

For instance, Rick Smith -- the CEO of Equifax from 2005 until 2017, whom many perceived as a strong performer -- was dismissed following an egregious data leakage scandal that received a commensurate amount of social scrutiny (what Busenbark and colleagues consider no severity gap). In contrast, Oscar Munoz -- the CEO of United Airlines who was appointed in 2015 and is also perceived as a strong performer -- retained his position after a high severity gap violation in which United Airlines was excoriated by conventional and social media following an airport's forcible removal of a single passenger from a United Airlines flight. These examples, as well as countless others, underscore the importance of the degree to which perceived scrutiny outstrips actual violation severity in determining whether strong-performing top actors are dismissed following a negative event.

John Schnatter, considered a weaker-performing CEO, was fired from Papa John's last year following a high severity gap violation. Busenbark says the company was on the decline when he was dismissed following some relatively innocuous comments that received a great deal of media backlash.

The research has broader implications for society and politics.

"In our current political climate, it is often difficult to find any parallel between the actual severity of a political transgression and the extent to which it resonates with conventional and social media," Busenbark says. "If media outlets and broader society on social media continually run with and sensationalize stories about politicians that are not actually that damaging, we theorize and find that Republicans and Democrats will circle around their political leaders and protect them to an even greater degree in the event that a more legitimate scandal emerges in the future." Much like when United Airlines encountered a large severity gap, politicians are often "raked over the coals" for relatively innocuous transgressions, while legitimate controversies sometimes never manifest in the public eye.

The study also finds that strong-performing leaders who are dismissed from their organizations after a scandal are more likely to secure at least an equivalent position elsewhere. However, top leaders do not secure equivalent or better employment elsewhere if dismissed after a high severity gap scandal, likely because outsiders prefer not to be associated with them.

BIRMINGHAM, Ala. - The heart cannot regenerate muscle tissue after a heart attack has killed part of the muscle wall. That dead tissue can strain surrounding muscle, leading to a lethal heart enlargement.

Biomedical engineers believe they can aid the failing heart by using pluripotent stem cells to grow heart muscle cells outside of the body, and then injecting those muscle cells or adding a patch made from those cells, at or near the site of the dead heart tissue. Experimental and clinical trial evidence with this approach has shown moderate improvement of the pumping ability of the heart's left ventricle.

However, the ability of the delivered cells to remuscularize the heart and improve cardiac function depends on the quality of those cells. A challenge has been low rates of engraftment by the transplanted cells.

University of Alabama at Birmingham researchers now report a simple method to improve the quality of the delivered cells, and they found that this method -- tested in a mouse heart attack model -- doubled the engraftment rate of the injected stem cell-derived cardiomyocytes. In a research letter in the journal Circulation, co-senior authors Ramaswamy Kannappan, Ph.D., and Jianyi "Jay" Zhang, M.D., Ph.D., say their robust approach to select functionally competent, intact-DNA cells from a heterogeneous population can be easily adopted in clinical settings to yield cells that are better able to repopulate the ischemic myocardium and improve the performance of a failing heart.

Zhang is chair of UAB Biomedical Engineering, a joint department of the UAB School of Medicine and School of Engineering, and holds the T. Michael and Gillian Goodrich Endowed Chair of Engineering Leadership. Kannappan is an assistant professor in the UAB Department of Biomedical Engineering.

Cardiac cell transplantation requires millions of stem cells or their differentiated derivatives. Cell propagation under accelerated growth conditions is a common way to get these large numbers of cells; but accelerated growth causes culture stress, including lethal DNA damage. These DNA-damaged cells are not suitable for cell transplantation and have to be removed from cell preparations.

The researchers found they could activate transcription factor p53 in induced pluripotent stem cells to selectively induce programmed cell death, or apoptosis, specifically in DNA-damaged cells, while sparing DNA damage-free cells. They used Nutlin-3a, an MDM2 inhibitor, to activate the p53. After Nutlin-3a treatment, the dead cells were washed from the culture, and the remaining DNA damage-free cells were cultured normally and differentiated into cardiomyocytes.

They then injected 900,000 of the derived cardiomyocytes into the border zone in the left ventricle of the mouse heart-attack model. Four weeks later, the researchers found a significantly higher engraftment rate, about 14 percent, in hearts that received the DNA damage-free cardiomyocytes. Engraftment of the control derived cardiomyocytes was about 7 percent.

"To our knowledge," Kannappan and Zhang said, "this is the first study to show that DNA damage-free induced pluripotent stem cells can be selected by p53 activation in induced pluripotent stem cell cultures, and that DNA damage-free cardiomyocytes have enhanced cardiac engraftment potential."

Previous research by others has shown that DNA-damaged senescent cells do not undergo cell death. Instead, they remain within the tissue, with altered functions that can change the tissue microenvironment and promote aging phenotypes of other cells. This may be one explanation for the engraftment advantage of DNA damage-free derived cardiomyocytes.

The method to remove DNA-damaged cells may have wider application, Kannappan says.

"As this is a small molecule based approach to select DNA damage-free cells," he said, "it can be applied to any type of stem cells, though selection conditions would need to be optimized and evaluated. Other stem cell approaches for diseases such as neurodegenerative diseases, brain and spinal cord injuries, and diabetes might benefit by adopting our method."

ANN ARBOR, Mich. - A new study, published in Annals of Internal Medicine, highlights the need for increased awareness of mental health disorders among adults with cerebral palsy.

"According to the Centers for Disease Control and Prevention, 1 in every 323 children in the United States has been identified as having cerebral palsy," says Daniel Whitney, Ph.D., an assistant professor of physical medicine and rehabilitation at Michigan Medicine.

"Much of the research regarding cerebral palsy focuses on childhood. However, with modern treatment advances, many of these children grow up to be adults," says Whitney, the study's lead author.

"Unfortunately, far less is known about the health and clinical care needed to promote healthy aging throughout the adult lifespan for this patient population."

Mark Peterson, Ph.D., M.S., FACSM, an associate professor of physical medicine and rehabilitation at Michigan Medicine and the senior author of the study, adds, "For example, how is this patient group's overall health and quality of life in adulthood? There isn't much research available to help answer this question and others."

In the study, Whitney and Peterson focus on mental health in adults with cerebral palsy and find that the patient population experiences an elevated prevalence of mental health disorders.

"And some of these mental health disorders were more pronounced in patients with cerebral palsy that also have comorbid neurodevelopmental disorders, such as intellectual disabilities, autism or epilepsy," Peterson says. "Which makes sense, as patients with cerebral palsy have an increased risk for secondary chronic conditions during childhood."

Examining data

Whitney and Peterson, both members of the University of Michigan Institute for Healthcare Policy and Innovation, examined insurance claims data for adults, both with cerebral palsy and those without the condition, and if the individual had a mental health disorder.

"We found that adults with cerebral palsy had higher age-standardized prevalence of mental health disorders compared to adults without cerebral palsy," Whitney says.

More specifically, the research team found male adults with cerebral palsy had higher prevalence of schizophrenic disorders (2.8% vs. 0.7%), mood affective disorders (19.5% vs. 8.1%), anxiety disorders (19.5% vs. 11.1%) and disorders of adult personality and behavior (1.2% vs. 0.3%), compared to their male adult counterparts.

"Female patients with cerebral palsy also exhibited similar or higher prevalence of those mental health disorders versus their female counterparts," Peterson says.

The research team did find one exception.

"We found that adult males with cerebral palsy exhibited higher rates of alcohol and/or opioid-related disorders compared to their male counterparts, whereas women with cerebral palsy did not exhibit higher rates of these disorders compared to their female counterparts," Peterson says.

Future implications

Whitney and Peterson agree that the results of this study demonstrate the need for additional focus on the mental health care of adults with cerebral palsy.

"Clinicians caring for adults with cerebral palsy need to be aware of the increased prevalence of mental health disorders in this patient population," Peterson says.

Whitney agrees, "We hope this study highlights the need for improved mental health screenings and access to mental health services and resources for these patients."

Hamilton, ON (August 8, 2019) - A large international study led by McMaster University shows that low risk pregnant women who intend to give birth at home have no increased chance of the baby's perinatal or neonatal death compared to other low risk women who intend to give birth in a hospital.

The results have been published by The Lancet's EClinicalMedicine journal.

"More women in well-resourced countries are choosing birth at home, but concerns have persisted about their safety," said Eileen Hutton, professor emeritus of obstetrics and gynecology at McMaster, founding director of the McMaster Midwifery Research Centre and first author of the paper. "This research clearly demonstrates the risk is no different when the birth is intended to be at home or in hospital."

The study examined the safety of place of birth by reporting on the risk of death at the time of birth or within the first four weeks, and found no clinically important or statistically different risk between home and hospital groups.

The study, which is the first systematic review and meta-analyses to use a previously published, peer-reviewed protocol for the research, used data from 21 studies published since 1990 comparing home and hospital birth outcomes in Sweden, New Zealand, England, Netherlands, Japan, Australia, Canada and the U.S. Outcomes from approximately 500,000 intended home births were compared to similar numbers of births intended to occur in hospital in these eight countries.

"Our research provides much needed information to policy makers, care providers and women and their families when planning for birth," said Hutton.

Dark matter, which researchers believe make up about 80% of the universe's mass, is one of the most elusive mysteries in modern physics. What exactly it is and how it came to be is a mystery, but a new Johns Hopkins University study now suggests that dark matter may have existed before the Big Bang.

The study, published August 7 in Physical Review Letters, presents a new idea of how dark matter was born and how to identify it with astronomical observations.

"The study revealed a new connection between particle physics and astronomy. If dark matter consists of new particles that were born before the Big Bang, they affect the way galaxies are distributed in the sky in a unique way. This connection may be used to reveal their identity and make conclusions about the times before the Big Bang too," says Tommi Tenkanen, a postdoctoral fellow in Physics and Astronomy at the Johns Hopkins University and the study's author.

While not much is known about its origins, astronomers have shown that dark matter plays a crucial role in the formation of galaxies and galaxy clusters. Though not directly observable, scientists know dark matter exists by its gravitation effects on how visible matter moves and is distributed in space.

For a long time, researchers believed that dark matter must be a leftover substance from the Big Bang. Researchers have long sought this kind of dark matter, but so far all experimental searches have been unsuccessful.

"If dark matter were truly a remnant of the Big Bang, then in many cases researchers should have seen a direct signal of dark matter in different particle physics experiments already," says Tenkanen.

Using a new, simple mathematical framework, the study shows that dark matter may have been produced before the Big Bang during an era known as the cosmic inflation when space was expanding very rapidly. The rapid expansion is believed to lead to copious production of certain types of particles called scalars. So far, only one scalar particle has been discovered, the famous Higgs boson.

"We do not know what dark matter is, but if it has anything to do with any scalar particles, it may be older than the Big Bang. With the proposed mathematical scenario, we don't have to assume new types of interactions between visible and dark matter beyond gravity, which we already know is there," explains Tenkanen.

While the idea that dark matter existed before the Big Bang is not new, other theorists have not been able to come up with calculations that support the idea. The new study shows that researchers have always overlooked the simplest possible mathematical scenario for dark matter's origins, he says.

The new study also suggests a way to test the origin of dark matter by observing the signatures dark matter leaves on the distribution of matter in the universe.

"While this type of dark matter is too elusive to be found in particle experiments, it can reveal its presence in astronomical observations. We will soon learn more about the origin of dark matter when the Euclid satellite is launched in 2022. It's going to be very exciting to see what it will reveal about dark matter and if its findings can be used to peak into the times before the Big Bang."

Fear can be measured in the brain and fearful life-threatening events can leave quantifiable long-lasting traces in the neural circuitry of the brain with enduring effects on behaviour, as shown most clearly in post-traumatic stress disorder (PTSD).

A new study by Western University demonstrates that the fear predators inspire can leave long-lasting traces in the neural circuitry of wild animals and induce enduringly fearful behaviour, comparable to effects seen in PTSD research.

The findings of this study, led by Western University's Liana Zanette, Scott MacDougall-Shackleton and Michael Clinchy, were published today in Scientific Reports - Nature.

For the first time, Zanette, her students and collaborators experimentally demonstrated that the effects predator exposure has on the neural circuitry of fear in wild animals can persist beyond the period of the immediate 'fight or flight' response and instead can remain measurable more than a week later, in animals exposed in the interim to natural environmental and social conditions.

"These results have important implications for biomedical researchers, mental health clinicians, and ecologists," explains Zanette, a biology professor in Western's Faculty of Science and a renowned expert on the ecology and neurobiology of fear. "Our findings support both the notion that PTSD is not unnatural, and that long-lasting effects of predator-induced fear with likely effects on fecundity and survival, are the norm in nature."

Retaining a powerful enduring memory of a life-threatening predator encounter is clearly evolutionarily beneficial if it helps the individual avoid such events in the future and a growing number of biomedical researchers have begun to propose that PTSD is the cost of inheriting an evolutionarily primitive mechanism that prioritizes survival over the quality of life.

Ecologists are recognizing that predators can affect prey numbers not just by killing prey, but by scaring them, as well. For example, Zanette and her collaborators have shown in a previous study that scared parents are less able to care for their young.

The long-lasting effects of fear on the brain demonstrated in this new study suggest predator exposure could impair parental behaviour for a prolonged period thereafter with greater negative effects on offspring survival than previously envisaged.

The team conducted the study on wild-caught, black-capped chickadees at Western's Advanced Facility for Avian Research (AFAR). For two days, individual birds were exposed to audio playbacks of the vocalizations of either predators or non-predators and then housed together in flocks outdoors for seven days during which time they were not exposed to any further experimental cues. After this seven-day period, enduringly fearful behaviour was quantified by measuring each individual's reaction to hearing a chickadee alarm call, and long-lasting effects on the neural circuitry of fear were assessed by measuring the levels of a genetic transcription factor in the brain (amygdala and hippocampus).

What happens inside a black hole stays inside a black hole, but what happens inside a black hole's "sphere of influence" - the innermost region of a galaxy where a black hole's gravity is the dominant force - is of intense interest to astronomers and can help determine the mass of a black hole as well as its impact on its galactic neighborhood.

New observations with the Atacama Large Millimeter/submillimeter Array (ALMA)
provide an unprecedented close-up view of a swirling disk of cold interstellar gas rotating around a supermassive black hole. This disk lies at the center of NGC 3258, a massive elliptical galaxy about 100 million light-years from Earth. Based on these observations, a team led by astronomers from Texas A&M University and the University of California, Irvine, have determined that this black hole weighs a staggering 2.25 billion solar masses, the most massive black hole measured with ALMA to date.

Though supermassive black holes can have masses that are millions to billions of times that of the Sun, they account for just a small fraction of the mass of an entire galaxy. Isolating the influence of a black hole's gravity from the stars, interstellar gas, and dark matter in the galactic center is challenging and requires highly sensitive observations on phenomenally small scales.

"Observing the orbital motion of material as close as possible to a black hole is vitally important when accurately determining the black hole's mass." said Benjamin Boizelle, a postdoctoral researcher at Texas A&M University and lead author on the study appearing in the Astrophysical Journal. "These new observations of NGC 3258 demonstrate ALMA's amazing power to map the rotation of gaseous disks around supermassive black holes in stunning detail."

Astronomers use a variety of methods to measure black hole masses. In giant elliptical galaxies, most measurements come from observations of the orbital motion of stars around the black hole, taken in visible or infrared light. Another technique, using naturally occurring water masers (radio-wavelength lasers) in gas clouds orbiting around black holes, provides higher precision, but these masers are very rare and are associated almost exclusively with spiral galaxies having smaller black holes.

During the past few years, ALMA has pioneered a new method to study black holes in giant elliptical galaxies. About 10 percent of elliptical galaxies contain regularly rotating disks of cold, dense gas at their centers. These disks contain carbon monoxide (CO) gas, which can be observed with millimeter-wavelength radio telescopes.

By using the Doppler shift of the emission from CO molecules, astronomers can measure the velocities of orbiting gas clouds, and ALMA makes it possible to resolve the very centers of galaxies where the orbital speeds are highest.

"Our team has been surveying nearby elliptical galaxies with ALMA for several years to find and study disks of molecular gas rotating around giant black holes," said Aaron Barth of UC Irvine, a co-author on the study. "NGC 3258 is the best target we've found, because we're able to trace the disk's rotation closer to the black hole than in any other galaxy."

Just as the Earth orbits around the Sun faster than Pluto does because it experiences a stronger gravitational force, the inner regions of the NGC 3258 disk orbit faster than the outer parts due to the black hole's gravity. The ALMA data show that the disk's rotation speed rises from 1 million kilometers per hour at its outer edge, about 500 light-years from the black hole, to well over 3 million kilometers per hour near the disk's center at a distance of just 65 light-years from the black hole.

The researchers determined the black hole's mass by modeling the disk's rotation, accounting for the additional mass of the stars in the galaxy's central region and other details such as the slightly warped shape of the gaseous disk. The clear detection of rapid rotation enabled the researchers to determine the black hole's mass with a precision better than one percent, although they estimate an additional systematic 12 percent uncertainty in the measurement because the distance to NGC 3258 is not known very precisely. Even accounting for the uncertain distance, this is one of the most highly precise mass measurements for any black hole outside of the Milky Way galaxy.

"The next challenge is to find more examples of near-perfect rotating disks like this one so that we can apply this method to measure black hole masses in a larger sample of galaxies," concluded Boizelle. "Additional ALMA observations that reach this level of precision will help us better understand the growth of both galaxies and black holes across the age of the universe."

Scientists at the German Center for Neurodegenerative Diseases (DZNE) have identified a group of proteins that help to regenerate damaged nerve cells. Their findings are reported in the journal Neuron.

It is commonly accepted that neurons of the central nervous system shut down their ability to grow when they no longer need it; this occurs normally after they have found their target cells and established synapses. However, recent findings show that old nerve cells have the potential to regrow and to repair damage similar to young neurons. The underlying mechanisms for this rejuvenation have now been uncovered in laboratory studies led by the team of Professor Frank Bradke at the DZNE's Bonn site together with scientists of the University of Bonn.

"Actually, this is quite surprising. It is by no means a matter of course that young and adult nerve cells share the same mechanisms," Bradke said. "Neurons show vigorous growth during embryonic development. Mature nerve cells, on the other hand, usually do not grow and fail to regenerate. Our study now reveals that although the ability to grow is inhibited in adult cells, the neurons keep the disposition for growth and regeneration." Bradke and coworkers discovered that certain proteins which initiate growth in young neurons are crucial for these processes. "These proteins are key regulators of growth competence, irrespective of developmental stage. They act on the cell's supporting structure and thus trigger dynamic processes, which are a prerequisite for growth and regeneration," the neurobiologist said.

Juvenile growth talents

In fact, neurons only show their growth talent during embryonic development. At this stage, they form long projections (called "axons") in order to connect and thus transmit signals. However, the ability to grow and thus regrow after injury dwindles when the nervous system reaches the adult stage. Only neurons of the "periphery", e. g. those in the arms and legs, retain a pronounced potential for mending damaged connections. However, if axons in the spinal cord are severed, they do not regrow: Consequently, the pathway for nerve impulses remains disturbed. This can cause paralysis and other serious disabilities.

A special protein family

"For quite some time, we have been wondering whether it is possible to reactivate the processes which manifest in the early developmental phase. This could be a way to trigger regeneration in adult neurons," Sebastian Dupraz said, a postdoctoral researcher in Bradke's lab and a leading author of the current study. In recent years the Bonn scientists identified various factors that influence the growth of neurons. Certain proteins - those of the "cofilin/ADF" family - proved to play a pivotal role: During embryonic development, these molecules control the formation of cell protuberances that ultimately evolve into axons. "In our recent study, we found that it is precisely these proteins that drive growth and regeneration, also in adult neurons," Dupraz said.

Molecular dissolution

The scientists found that the growth and regrowth of neurons is fueled by the turnover of actin filaments. These string shaped molecules belong to the molecular scaffold that gives the cell its form and stability. The proteins of the cofilin/ADF family partially dissolve this corset. It is only through this breakup that the structure of the cell can change - and thus the neuron can grow and regenerate. "An approach for future regenerative interventions could be to target actin," DZNE scientist Barbara Schaffran, another leading author of the current study, mentions.

The researchers observed these processes in the nerve cells of mice and rats. The neurons examined belonged to the "dorsal root ganglion". This is a bundle of neurons that interfaces the spinal cord with the peripheral nervous system. The cells located there each have two axons: a central and a peripheral. The peripheral axon can regenerate after damage. It has long been known that the central axon can also regrow; but only if its peripheral counterpart has previously been lesioned. "Why the sequence is like this is still not exactly known," Bradke said. "We will be looking into this in the future."

Contribution to fundamental research

Step by step, the Bonn scientists are trying to understand what makes neurons grow and regenerate. It is a lengthy process. Bradke is therefore dampening expectations of rapid progress in the treatment of spinal cord injuries. "We do research in order to set the basis for future therapies. But sadly, you have to be patient until new treatment approaches develop. That's a long way to go," he said.