Culture

Stanford University School of Medicine researchers have demonstrated that gene therapy can be effective without causing a dangerous side effect common to all gene therapy: an autoimmune reaction to the normal protein, which the patient's immune system is encountering for the first time.

The researchers showed this in a mouse model that accurately recapitulates Duchenne muscular dystrophy. One in every 5,000 boys is born with this crippling disease, which leaves patients wheelchair-bound by mid-adolescence and is typically fatal by young adulthood. It stems from a genetic defect that deprives skeletal and cardiac muscles of a working version of a protein called dystrophin.

"Gene therapy is on the cusp of becoming a mainstream approach for treating single-gene disorders," said Lawrence Steinman, MD, professor of neurology and neurological sciences and of pediatrics at Stanford. "But there's a catch: If you give a gene that's a recipe for a normal protein to someone with a faulty version of the gene, whose body never made the normal protein before, that person's immune system will mount a reaction -- in some cases, a lethal one -- to the normal protein, just as it would to any foreign protein. We think we've solved that problem."

The findings are described in a study to be published online Sept. 3 in the Proceedings of the National Academy of Sciences. Steinman, who holds the George A. Zimmermann Professorship, is the study's senior author. The lead author is senior research scientist Peggy Ho, PhD.

Going viral

Duchenne muscular dystrophy is the result of a single defective gene, making it an excellent candidate for gene therapy in which a patient's faulty gene is replaced with the correct version. One way to do this is by co-opting viruses, which are simple entities that are adept at infecting cells and then forcing every invaded cell's reproductive machinery to copy their own viral genes. For gene therapy, viruses are modified by ridding them of unwanted genes, retaining the ones necessary for infectivity and adding the therapeutic gene to be delivered to a patient.

The gene encoding dystrophin is far too big for a gene-hauling virus to take onboard. Fortunately, a mere fraction of the entire gene is enough to generate a reasonably functional version of dystrophin, called microdystrophin. The abridged gene fits snugly into a viral delivery vehicle designed some time ago by Jeffrey Chamberlain, PhD, a co-author of the study and a professor of neurology, medicine and biochemistry at the University of Washington.

Inducing tolerance

But there's still that sticky autoimmunity problem. To get around it, Steinman and his colleagues spliced the gene for microdystrophin into a different kind of delivery vehicle called a plasmid.

Plasmids are tiny rings of DNA that bacteria often trade back and forth to disseminate important traits, such as drug resistance, among one another. The particular bacterial plasmid the investigators co-opted ordinarily contains several short DNA sequences, or motifs, that the immune system recognizes as suspicious and to which it mounts a strong response.

But some years ago, Steinman and a few other Stanford scientists -- including Ho and study co-author William Robinson, MD, PhD, professor of immunology and rheumatology -- figured out how to replace those troublesome DNA motifs with another set of DNA sequences that, far from exacerbating the immune response, subdue it. This immune-tolerance-inducing plasmid has been deployed in clinical trials for two different autoimmune conditions, with promising results.

For the new study, the researchers used a one-two punch to deliver gene therapy and protection against autoimmunity to the mice: viral delivery of the microdystrophin gene, followed by the plasmid-assisted induction of tolerance to microdystrophin.

Fifteen 6-week-old mice -- an age roughly equivalent to that of a young child -- bioengineered to lack functioning dystrophin were injected with the virus carrying microdystrophin. Starting a week later, they were divided into three groups and given weekly injections for 32 weeks of either a dummy solution; the dummy solution plus the tolerance-inducing plasmid absent the microdystrophin gene; or the plasmid with the microdystrophin gene.

At the end of the 32-week period, by which time the mice were the human equivalent of young adults, the ones that got the microdystrophin-loaded plasmid had significantly greater muscular strength and substantially more dystrophin-producing muscle fibers. They had lower levels of key bloodborne signaling chemicals that carry inflammatory messages between immune cells, and they had weakened antibody responses to normally immunogenic portions of microdystrophin.

"It's still early days here -- this was, after all, a mouse experiment -- but it seems we can induce tolerance to a wide assortment of formerly immunogenic proteins by inserting the gene for the protein of interest into the plasmid," Steinman said. "We've seen this with the insulin precursor, in people who have Type 1 diabetes, and with myelin, in people who have multiple sclerosis. It now looks as if the concept may hold for gene therapy, too."

Children conceived through assisted reproductive technologies may be at an increased risk of developing arterial hypertension early in life, among other cardiovascular complications, according to a Swiss study published today in the Journal of the American College of Cardiology.

Developed in 1978, assisted reproductive technologies (ART) has helped millions of individuals and families who cannot conceive naturally. The most common ART methods are in vitro fertilization and intracytoplasmic sperm injection, which can expose the gamete and embryo to a variety of environmental factors before implantation. Children conceived using ART make up 1.7 percent of all infants born in the United States every year and currently over six million persons worldwide.

The study authors assessed the circulatory system of 54 young, healthy ART adolescents (mean age 16) by measuring ambulatory blood pressure, as well as plaque build-up, blood vessel function and artery stiffness. Body mass index, birth weight, gestational age, and maternal BMI, smoking status and cardiovascular risk profile were similar between the ART adolescents and 43 age- and sex-matched control participants.

Through 24-hour ambulatory blood pressure monitoring, researchers discovered that ART adolescents had both a higher systolic and diastolic blood pressure than the control participants of natural conception at 119/71 mmHg versus 115/69, respectively. Most importantly, eight of the ART adolescents reached the criteria for the diagnosis of arterial hypertension (over 130/80 mmHg) whereas only one of the control participants met the criteria.

"The increased prevalence of arterial hypertension in ART participants is what is most concerning," said Emrush Rexhaj, MD, director of Arterial Hypertension and Altitude Medicine at Inselspital, University Hospital in Bern, Switzerland and the lead author of the study. "There is growing evidence that ART alters the blood vessels in children, but the long-term consequences were not known. We now know that this places ART children at a six times higher rate of hypertension than children conceived naturally."

The authors also studied these participants five years before this study and found that the arterial blood pressure between ART and control children was not different.

"It only took five years for differences in arterial blood pressure to show," Rexhaj said. "This is a rapidly growing population and apparently healthy children are showing serious signs of concern for early cardiovascular risk, especially when it comes to arterial hypertension."

In an accompanying editorial, Larry A. Weinrauch, MD, cardiologist at Mount Auburn Hospital said that the study's small cohort may understate the importance of this problem for ART adolescents, especially since multiple birth pregnancies and maternal risk factors (such as eclampsia, chronic hypertension and diabetes) were excluded from the study.

"Early study, detection and treatment of ART conceived individuals may be the appropriate course of preventative action," Weinrauch said. "We need to be vigilant in the development of elevated blood pressure among children conceived through ART to implement early lifestyle-based modifications and, if necessary, pharmacotherapy."

Limitations of this study include that only single-birth children were studied, as well as that participants were recruited from one procreation center. Prematurity, low birth weight and preeclampsia (all known cardiovascular risk factors) were excluded from the study. These limitations may have resulted in a lower cardiovascular risk among the participants compared to the overall ART population.

What if social behavior affected the progression of even noncontagious diseases? This is precisely what has been demonstrated by French CNRS teams,(1) with support from the French National Research Institute for Sustainable Development (IRD), Paris-Sud University, the University of Montpellier, the French Alternative Energies and Atomic Energy Commission (CEA), and colleagues from Spain and Australia. Using a fly model of intestinal cancer, the researchers have shown that disease progression is impacted both by social isolation--which has a negative effect--and the composition of the social group with which individuals associate. Their findings are published in Nature Communications (September 3, 2018).

For many animals, humans included, social behavior can play a critical role in the survival of individuals. The effect that interactions between individuals can have on the spread of communicable diseases is well known. But is there any connection between social interactions and the progression, within sick individuals, of noncommunicable diseases like cancers? To address this question, the scientists chose the fruit fly Drosophila melanogaster as their research model. Control of the social environment and experimental induction of disease (an intestinal cancer in this case) are both easily achieved when working with drosophilas. The team sought to determine whether the social environment of diseased individuals altered the speed of tumor progression and if these flies could choose their social environment to slow this progression.

They observed that disease progression in sick flies was faster in social isolation than when interacting with other flies. Even more surprisingly, the very structure of a diseased fly's social group could affect the progression of its illness. When a sick fly is in the company of healthy ones, its tumor spreads more quickly than when interacting with other sick individuals. Detailed analyses of interactions between flies, monitored through video, suggest that sick flies interact less with healthy ones in their presence--effectively exhibiting a sort of isolation in the midst of the healthy crowd.

It is interesting to note that, when given the choice between a sick or healthy group, a sick fly will choose to join other sick flies--at least during the early stages of illness. Once the tumor is in an advanced state, the fly no longer shows any preference. The behavior of healthy flies is different. Though they make no distinction between healthy flies and sick flies at an early stage of disease, they will avoid sick flies with more advanced tumors and prefer the company of other healthy flies. The exact reasons for such avoidance are still poorly understood and currently under study. It may reflect a nonspecific response to the risks posed by diseases in general--such as contagion, compromised reproductive potential, and greater vulnerability to predators.

Though these findings cannot yet be extrapolated to humans, they suggest that social environment plays a substantial, even major, role in the development of a disease like cancer.

Abnormal levels of more than two dozen metabolites -- chemicals produced in the body as it breaks down fats, proteins and carbohydrates -- can reliably predict which Sept. 11 firefighters developed lung disease and which did not, a new analysis shows.

Researchers say the results, published by NYU School of Medicine researchers in the journal BMJ Open Respiratory Research online Sept. 4, could lead to metabolic tests for early detection of lung damage in all disaster victims exposed to fine particles from fire, smoke, and toxic chemicals, not just 9/11 firefighters.

The study, researchers say, offers the first evidence that metabolite blood tests conducted within months of the disaster could still help in the detection of obstructive airway disease, or OAD. Such analysis could aid in diagnosing OAD in the roughly 9,000 firefighters exposed to toxic chemicals at the World Trade Center (WTC) on Sept. 11, 2001, or during the cleanup that followed.

Senior study investigator Anna Nolan, MD, says the team hopes to develop a precise chemical profile of firefighters most at risk of developing OAD -- including asthma, chronic bronchitis, and/or emphysema -- by analyzing fluid samples from 9/11 firefighters not included in the current study.

Nolan, an associate professor in the Department of Medicine at NYU Langone Health, says her team's findings raise the possibility that correcting metabolic imbalances -- through dietary changes or food supplements -- could ward off or even reverse loss of lung function. Already, the team has plans to test a low-calorie Mediterranean diet, known for its ability to rebalance the body's metabolites, for its potential effects on the firefighters' lung health.

"Healthy lung function is essential for everyone, but especially firefighters, to carry out their work," says Nolan. She says all firefighters, including those exposed to toxic chemicals on or after 9/11, are routinely monitored through annual physical and medical exams, and "decreases in their lungs' strength to inhale or blow out air are a sign of respiratory ill health."

Nolan says previous research has shown that nearly one in 10 firefighters exposed to dust at the WTC site is showing signs of lung injury. She says the WTC dust was laden with dangerous heavy metals, such as chromium and mercury, in addition to powdered concrete and toxic fibrous glass, asbestos, and components of jet fuel. When firefighters inhaled some of the dust at the disaster site, she says, it amounted to a slow chemical burning of their lung tissue that, in turn, led to chronic inflammation and lung injury.

For the current study, led by co-investigators George Crowley and Sophia Kwon, DO, MPH, the NYU Langone team analyzed blood levels of 580 metabolites frequently found in the body. All samples came from 9/11 firefighters who were tested within seven months of the disaster, and whose lung function has been tested annually ever since. Researchers matched 15 firefighters whose lung function had sharply declined by 2015 with 15 whose lung function had remained healthy, despite similar levels of exposure to WTC dust. Advanced computer software was then used to analyze the large volume of metabolite data.

When researchers plotted all metabolites on graphs, various chemical groups stood out as highly predictive of the majority of cases of OAD and lung injury.

Key among them were:

decreases in sphingolipids, such as sphingosine 1-phosphate, a fat that has previously been linked to higher rates of asthma and found to trigger inflammation;

declines in branched-chain amino acids, the building blocks of proteins, including leucine and valine, whose supplementation has in previous research been shown to counter chronic obstructive pulmonary disease (COPD);

increases in levels of stress hormones, especially vanillylmandelate, which may lead to elevated levels of fatty acids, potentially inducing inflammation.

Nolan says it is likely that metabolic imbalances contribute to the chronic inflammation that underlies most OAD and lung injury.

Boston-- Experiencing homelessness at any time during the pre- or postnatal period can negatively affect a young child's health. Researchers at Children's HealthWatch, based out of Boston Medical Center (BMC), found that children who experienced both pre- and post-natal homelessness and those who experienced homelessness for longer than six months were at highest risk of negative health outcomes. These findings, published in Pediatrics, illustrate the urgent need to intervene and rapidly house children and families experiencing homelessness to minimize the negative health outcomes.

Researchers interviewed 20,000 low-income caregivers of children under four years old who visited outpatient pediatric clinics in five cities across the U.S. between 2009 and 2015. The researchers asked questions to determine if a child experienced homelessness, how long they experienced homelessness, and when in the child's life they experienced homelessness. They then conducted an assessment of the child determining their overall condition; if/how often the child was hospitalized; if a child was over or underweight; and if the child experienced any developmental delays.

More than three percent of caregivers reported experiencing prenatal homelessness, 3.7 percent reported postnatal homelessness, and 3.5 percent reported both.

The study found children who experienced homelessness for more than six months were at high risk of poor health outcomes. Also at high risk were children who experienced homelessness during both the pre- and post-natal period, showing that the earlier and longer in development a child experiences homelessness may have a larger cumulative toll of poor health and development outcomes.

"These findings back up what we already knew about how the stress of homelessness affects children's heath," said Megan Sandel, MD, MPH, pediatrician at BMC and lead investigator at Children's HealthWatch, "but this helps us determine which children are at greatest risk, and makes the argument that policymakers and providers need to intervene to change the trajectory of a child's development."

Researchers also note the toll poor health outcomes caused by child homelessness can exact on health systems. Greater health care utilization, increased hospitalizations, and need for developmental interventions creates substantial family and societal health care expenses.

"As pediatricians, we should be regularly screening families for housing insecurity, including past history and future risk of homelessness," said Deborah Frank, MD, director of the GROW Clinic at BMC and senior author on the study. "Interventions that prevent homelessness for families and pregnant women can be extremely effective, and with data on the housing status of our patients, we can better advocate for more resources to drive innovations in addressing housing instability."

A genetic disruption strategy developed by University of Colorado Boulder researchers effectively stymies the evolution of antibiotic-resistant bacteria such as E. coli, giving scientists a crucial leg up in the ongoing battle against deadly superbugs.

These multidrug-resistant pathogens--which adapt to current antibiotics faster than new ones can be created--infect nearly 2 million people and cause at least 23,000 deaths annually in the U.S., according to data from the Centers for Disease Control.

In an effort to develop a sustainable long-term solution, CU Boulder researchers created the Controlled Hindrance of Adaptation of OrganismS (CHAOS) approach, which uses CRISPR DNA editing techniques to modify multiple gene expressions within the bacteria cells, stunting the pathogen's central processes and thwarting its ability to evolve defenses.

"We now have a way to cut off the evolutionary pathways of some of the nastiest bugs and potentially prevent future bugs from emerging at all," said Peter Otoupal, lead author of the study and a doctoral researcher in CU Boulder's Department of Chemical and Biological Engineering (CHBE).

The CHAOS research is the culmination of work that began in 2013, when Otoupal and his colleagues began searching for genes that could act as a cellular kill switch for E. coli. When the scientists tweaked one gene at a time, the bacteria could adapt and survive. But when they altered two or more genes at once, the cell got weaker.

"We saw that when we tweaked multiple gene expressions at the same time--even genes that would seemingly help the bacteria survive--the bacteria's fitness dropped dramatically," Otoupal said.

The CHAOS method takes advantage of this effect, pulling multiple genetic levers in order to build up stress on the bacterial cell and eventually trigger a cascading failure, leaving the bug more vulnerable to current treatments. The technique does not alter the bug's DNA itself, only the expression of individual genes, similar to the way a coded message is rendered useless without the proper decryption.

"You can think of it in terms of a series of escalating annoyances to the cell that eventually cause it to weaken," said Anushree Chatterjee, senior author of the study and an assistant professor in CHBE. "This method offers tremendous potential to create more effective combinatorial approaches."

Although E. coli has nearly 4,000 individual genes, the exact gene modification sequence appears to matter less than the sheer number of genes that are disrupted, Otoupal said. Still, the researchers plan to continue optimizing the CHAOS method to seek out the most efficient disruptions.

The findings are outlined today in the journal Nature Communications Biology and could open new research avenues on how to best restrict a pathogen's antibiotic resistance.

"Diseases are very dynamic, so we need to design smarter therapies that can gain control over their rapid adaptation rates," Chatterjee said. "The emphasis in our lab is demonstrating the efficacy of these methods and then finding ways to translate the technology to modern clinical settings."

"In the past, nobody really considered that it might be possible to slow down evolution," Otoupal said. "But like anything else, evolution has rules and we're starting to learn how to use them to our advantage."

For the first time, Temple University researchers have used machine learning to rank the most important determinants of future affluence. Education and occupation were the best predictors -- but surprisingly, a person's ability to delay instant gratification was also among the most important determinants of higher income, beating age, race, ethnicity and height. Published in Frontiers in Psychology, the study suggests that interventions to improve this "delay discounting" could have literal payoffs in terms of higher income attainment.

Many factors are related to how much money a person will earn, including age, occupation, education, gender, ethnicity and even height. Behavioral variables are also implicated, such as one relating to the famous "marshmallow test." This study of delay discounting, or how much a person discounts the value of future rewards compared to immediate ones, showed children with greater self-control were more likely to have higher salaries later in life.

But the study's lead author, Dr William Hampton, now at the University of St. Gallen in Switzerland, says more traditional ways of analyzing data have been unable to indicate which of these factors are more important than others.

"All sorts of things predict income. We knew that this behavioral variable, delay discounting, was also predictive -- but we were really curious how it would stack up against more common-sense predictors like education and age. Using machine learning, our study was the first to create a validated rank ordering of age, occupation, education, geographic location, gender, race, ethnicity, height, age and delay discounting in income prediction."

Traditional methods used by psychologists (such as correlations and regression) haven't allowed for a simultaneous comparison of different factors relating to an individual's affluence. This study collected a large amount of data -- from more than 2,500 diverse participants -- and split them into a training set and a test set. The test set was put aside while the training set produced model results. The researchers then went back to the test set to test the accuracy of their findings.

Unsurprisingly, the models indicated that occupation and education were the best predictors of high income, followed by location (as determined by zip code) and gender -- with males earning more than females. Delay discounting was the next most-important factor, being more predictive than age, race, ethnicity or height.

Dr Hampton hopes the research approach will be part of a new era in data analysis. "This was amazing because it allowed us to check our findings and replicate them, giving us much greater confidence that they were accurate. This is particularly important given the recent wave of findings across science that do not seem to replicate. Using this machine learning approach could lead to more research that replicates -- and we hope this spurs the use of more sophisticated analytic approaches in general."

The study's authors caution that the data sample was purposely limited to the United States and it is possible that the rank order of variables that predict salary may differ in other countries. Dr Hampton says he is looking forward to exploring this analytical approach in a broader context.

"I would love to see a replication of this study in another culture. I also would be very interested in future studies aiming to reduce delay discounting. There is much debate about whether delay discounting is a stable trait or whether it is malleable -- longitudinal studies could help settle that."

Finally, Dr Hampton has an interesting observation for parents, "if you want your child to grow up to earn a good salary, consider instilling in them the importance of passing on smaller, immediate rewards in favor of larger ones that they have to wait for. This is probably easier said than done, as very few people naturally enjoy waiting, but our results suggest that those who develop the ability to delay gratification are likely investing in their own earning potential."

LAWRENCE -- American gun owners in recent years have exhibited higher levels of political participation, not only in voting but in donating money to candidates and contacting elected officials, according to a study by University of Kansas political scientists.

"Part of the reason majority opinions on gun control legislation aren't turning into policy is that gun owners are a very strong political group who hold a lot of weight and hold a lot of influence despite being a minority in American politics," said Abbie Vegter, a graduate student in political science.

Vegter is collaborating on the research with KU political science professors Don Haider-Markel and Mark Joslyn. They will present their findings, "Motivated Voices: Gun Ownership and the Propensity for Political Participation," today, Sept. 2, as part of the American Political Science Association's annual meeting in Boston.

Haider-Markel and Joslyn have published several studies on gun politics in recent decades.

In the recent study, the researchers examined the political behavior of gun owners versus non-gun owners in presidential election years from 1972 to 2012. Primarily, they found that gun owners have increasingly become more politically active during that time. The findings could be key in determining why major gun control legislation in Congress has remained elusive, even after mass shootings such as Newtown in 2012 and others, even when a majority of people tend to support stricter gun laws.

"Our major conclusion establishes gun owners as a distinct social group, and we see how that social group influences their likelihood of participating in politics," Vegter said.

Much of political conversation surrounding guns tends to focus on large groups like the National Rifle Association's influence, but Vegter said the study's results paint a different picture.

"Only one in five gun owners belong to the NRA, so we think there is something else going on than just the NRA when it comes to mobilization," she said.

One explanation could be shifting reasons for owning a gun and how more people tend to see it as part of their identity.

"Owning a gun for hunting doesn't necessarily mean being a hunter is a core part of your identity," she said. "But owning a gun because you think it's an essential right guaranteed in the Constitution is more a part of your political identity. It's something more attached from the get-go to politics."

Vegter said the researchers are still exploring what has driven this shift in attitude among gun owners, whether it was in response to past gun control legislation at the state level or a reaction to certain candidates who were elected who had stronger views about gun control.

Conservatives seem to have done a better deal at realizing this trend and seeking to politically mobilize gun owners in campaign ads and other actions, she said.

"There are a couple of lessons. For individuals, especially individual gun control advocates, in order to make a difference, you need to match this level of mobilization and participation," Vegter said. "There is also a lesson there for politicians who I think traditionally have not seen gun owners as a political group to be addressed."

One development to watch will be the level of activity, especially among students who survived the Feb. 14 shooting at Marjory Stoneman Douglas High School in Parkland, Florida. Many of them have advocated in campaigns and in national media for stricter gun control policies, which has kept the issue in the forefront longer than what typically occurs after a high-profile mass shooting, she said.

"There has been this sustained attention," Vegter said, "and I think the true test will be that mobilization piece."

Harvard University researchers have developed a new printing method that uses sound waves to generate droplets from liquids with an unprecedented range of composition and viscosity. This technique could finally enable the manufacturing of many new biopharmaceuticals, cosmetics, and food and expand the possibilities of optical and conductive materials.

"By harnessing acoustic forces, we have created a new technology that enables myriad materials to be printed in a drop-on-demand manner," said Jennifer Lewis, the Hansjorg Wyss Professor of Biologically Inspired Engineering at the Harvard John A. Paulson School of Engineering and Applied Sciences and the senior author of the paper.

Lewis is also a Core Faculty Member at the Wyss Institute for Biologically Inspired Engineering and the Jianming Yu Professor of Arts and Sciences at Harvard.

The research is published in Science Advances.

Liquid droplets are used in many applications from printing ink on paper to creating microcapsules for drug delivery. Inkjet printing is the most common technique used to pattern liquid droplets, but it's only suitable for liquids that are roughly 10 times more viscous than water. Yet many fluids of interest to researchers are far more viscous. For example, biopolymer and cell-laden solutions, which are vital for biopharmaceuticals and bioprinting, are at least 100 times more viscous than water. Some sugar-based biopolymers could be as viscous as honey, which is 25,000 times more viscous than water.

The viscosity of these fluids also changes dramatically with temperature and composition, makes it even more difficult to optimize printing parameters to control droplet sizes.

"Our goal was to take viscosity out of the picture by developing a printing system that is independent from the material properties of the fluid," said Daniele Foresti, first author of the paper, the Branco Weiss Fellow and Research Associate in Materials Science and Mechanical Engineering at SEAS and the Wyss Institute.

To do that, the researchers turned to acoustic waves.

Thanks to gravity, any liquid can drip -- from water dripping out of a faucet to the century-long pitch drop experiment. With gravity alone, droplet size remains large and drop rate difficult to control. Pitch, which has a viscosity roughly 200 billion times that of water, forms a single drop per decade.

To enhance drop formation, the research team relies on generating sound waves. These pressure waves have been typically used to defy gravity, as in the case of acoustic levitation. Now, the researchers are using them to assist gravity, dubbing this new technique acoustophoretic printing.

The researchers built a subwavelength acoustic resonator that can generate a highly confined acoustic field resulting in a pulling force exceeding 100 times the normal gravitation forces (1 G) at the tip of the printer nozzle -- that's more than four times the gravitational force on the surface of the sun.

This controllable force pulls each droplet off of the nozzle when it reaches a specific size and ejects it towards the printing target. The higher the amplitude of the sound waves, the smaller the droplet size, irrespective of the viscosity of the fluid.

"The idea is to generate an acoustic field that literally detaches tiny droplets from the nozzle, much like picking apples from a tree," said Foresti.

The researchers tested the process on a wide range of materials from honey to stem-cell inks, biopolymers, optical resins and, even, liquid metals. Importantly, sound waves don't travel through the droplet, making the method safe to use even with sensitive biological cargo, such as living cells or proteins.

"Our technology should have an immediate impact on the pharmaceutical industry," said Lewis. "However, we believe that this will become an important platform for multiple industries."

"This is an exquisite and impactful example of the breadth and reach of collaborative research," said Dan Finotello, director of NSF's MRSEC program. "The authors have developed a new printing platform using acoustic-forces, which, unlike in other methods, are material-independent and thus offer tremendous printing versatility. The application space is limitless."

The so-called CB1 receptor is responsible for the intoxicating effect of cannabis. However, it appears to act also as a kind of "sensor" with which neurons measure and control the activity of certain immune cells in the brain. A recent study by the University of Bonn at least points in this direction. If the sensor fails, chronic inflammation may result - probably the beginning of a dangerous vicious circle. The publication appears in the journal Frontiers in Molecular Neuroscience.

The activity of the so-called microglial cells plays an important role in brain aging. These cells are part of the brain's immune defense: For example, they detect and digest bacteria, but also eliminate diseased or defective nerve cells. They also use messenger substances to alert other defense cells and thus initiate a concerted campaign to protect the brain: an inflammation.

This protective mechanism has undesirable side effects; it can also cause damage to healthy brain tissue. Inflammations are therefore usually strictly controlled. "We know that so-called endocannabinoids play an important role in this", explains Dr. Andras Bilkei-Gorzo from the Institute of Molecular Psychiatry at the University of Bonn. "These are messenger substances produced by the body that act as a kind of brake signal: They prevent the inflammatory activity of the glial cells."

Endocannabinoids develop their effect by binding to special receptors. There are two different types, called CB1 and CB2. "However, microglial cells have virtually no CB1 and very low level of CB2 receptors," emphasizes Bilkei-Gorzo. "They are therefore deaf on the CB1 ear. And yet they react to the corresponding brake signals - why this is the case, has been puzzling so far."

Neurons as "middlemen"

The scientists at the University of Bonn have now been able to shed light on this puzzle. Their findings indicate that the brake signals do not communicate directly with the glial cells, but via middlemen - a certain group of neurons, because this group has a large number of CB1 receptors. "We have studied laboratory mice in which the receptor in these neurons was switched off," explains Bilkei-Gorzo. "The inflammatory activity of the microglial cells was permanently increased in these animals."

In contrast, in control mice with functional CB1 receptors, the brain's own defense forces were normally inactive. This only changed in the present of inflammatory stimulus. "Based on our results, we assume that CB1 receptors on neurons control the activity of microglial cells," said Bilkei-Gorzo. "However, we cannot yet say whether this is also the case in humans."

This is how it might work in mice: As soon as microglial cells detect a bacterial attack or neuronal damage, they switch to inflammation mode. They produce endocannabinoids, which activate the CB1 receptor of the neurons in their vicinity. This way, they inform the nerve cells about their presence and activity. The neurons may then be able to limit the immune response. The scientists were able to show that neurons similarly regulatory the other major glial cell type, the astroglial cells.

During ageing the production of cannabinoids declines reaching a low level in old individuals. This could lead to a kind of vicious circle, Bilkei-Gorzo suspects: "Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode. More regulatory neurons die as a result, so the immune response is less regulated and may become free-running."

It may be possible to break this vicious circle with drugs in the future. It is for instance hoped that cannabis will help slow the progression of dementia. Its ingredient, tetrahydrocannabinol (THC), is a powerful CB1 receptor activator - even in low doses free from intoxicating effect. Last year, the researchers from Bonn and colleagues from Israel were able to demonstrate that cannabis can reverse the aging processes in the brains of mice. This result now suggest that an anti-inflammatory effect of THC may play a role in its positive effect on the ageing brain.

Washington, DC - August 31, 2018 - In an unexpected research finding infections with the intestinal parasite, Cryptosporidium parvum, worsened in mice that had been given a probiotic. The research was published in Applied and Environmental Microbiology, a journal of the American Society for Microbiology.

As compared to control mice, the probiotic-consuming mice excreted more parasites in their feces, and their intestinal microflora were different from those of the control mice. However, both sets of microflora were composed of genera that normally are present in the gut, and the mechanisms responsible for the observed probiotic effect are unclear, said corresponding author, Giovanni Widmer, PhD, whose graduate student, Bruno Oliveira, ran the experiments.

Contrary to expectations, "we found that consumption of a commercially available probiotic actually increased the severity of the infection," said Dr. Widmer, who is Professor of Infectious Disease & Global Health, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA.

Cryptosporidiosis is a major cause of infant diarrhea in developing nations. It killed an estimated 48,000 people worldwide in 2016, and caused the loss of more than 4.2 million disability-adjusted life-years, according to The Lancet, a medical journal. There are neither drugs to treat cryptosporidiosis, nor vaccines to prevent it. (image: high magnification micrograph of cryptosporidium infection, Wikimedia Commons)

Antibiotics, which often perturb or even deplete the normal intestinal microbiota, can thus render individuals more vulnerable to intestinal infections. Conversely, a healthy microbiome can prevent such infections, or reduce their severity. Reasoning along these lines, the researchers posited that a probiotic containing live microorganisms that are found in healthy intestines could reduce the severity of cryptosporidiosis in a mouse model.

"Mitigating the disease's severity may be sufficient to prevent diarrhea, or shorten its duration, and enable the immune system to naturally control the infection," said Dr. Widmer.

Despite an outcome that was contrary to the working hypothesis, the results demonstrate that it may be possible to develop probiotics to mitigate cryptosporidiosis. Prior to the experiment, "we didn't know if cryptosporidium growth in the gut could be affected by diet," said Dr. Widmer. "The goal is now to find a mechanistic link between microflora and cryptosporidium proliferation, and ultimately design a simple nutritional supplement which helps the body fight the infection."

"Identifying specific mechanisms that alter pathogen virulence in response to diet may enable the development of simple pre- or probiotics capable of modifying the composition of the microbiota to reduce the severity of cryptosporidiosis," said Dr. Widmer.

In the United States, four out of five older adults have multiple chronic health conditions. Many of these people rely on the active support of a family caregiver to help manage their conditions.

Studies of older adults with dementia and their caregivers have shown that very often, the older adult's desire to be self-sufficient often clashes with the caregiver's concerns about the individual's safety. However, researchers have also identified areas of friction among older adults who do not have dementia and their caregivers.

For example, according to one study among older adults who have severe heart disease, these individuals don't appreciate unwanted or excessive phone contact--or advice they haven't requested--from family and friends. In another study, older adults with lupus (an autoimmune disease caused when your immune system attacks your own body tissue) said they'd received advice from friends and family that they felt wasn't well-informed. They also reported they received support that felt "overprotective."

Noting that we need more understanding of caregiver and care recipient relationships, a research team designed a study using interviews with caregivers and the older adults receiving care. These interviews were designed to explore experiences, attitudes, and preferences about caregiving relationships. The study appeared in the Journal of the American Geriatrics Society.

The researchers recruited older adults from primary-care and specialty clinics and from assisted-living facilities in Connecticut. The care recipients were 65-years-old or older, had more than two chronic conditions, did not have problems thinking or making decisions, and had an unpaid caregiver (relative or friend) who was involved in their health care.

The older adults were first asked to name their chronic conditions, and then to describe how their caregivers helped them manage those conditions. Researchers also learned about the care recipients' reactions to the assistance they received. Caregivers were invited to respond to their care recipients' answers, provide their own examples, and discuss how they felt about the assistance they provided.

After the interview, the care recipients completed a questionnaire about age, gender, race, education, marital status, living arrangements, and their relationship to their caregivers. Caregivers completed a separate questionnaire about their age, gender, race, education, marital and employment status, and living arrangements.

The care recipients were around 82-years-old; most were white and female. Caregivers were around 70-years-old, two-thirds were women, and most were either a spouse or an adult child of the person receiving care.

The researchers learned about caregiving activities that were common to most caregiver/care recipient pairs. These included managing medications, coordinating healthcare appointments, managing paid caregivers, and speaking with medical professionals.

Relationships that were "supportive" included these behaviors:

Agreement about caregiver's level of involvement. Caregivers were responsive to the care recipient's desired level of assistance. In visits with healthcare providers, for example, caregivers were mindful of the care recipient's desire to speak directly to the provider but asked clarifying questions to make sure they understood all the information.

Mutual understanding. Care recipients tried to be less demanding of caregivers by being "good patients" and following their treatment regimens. Caregivers acknowledged the challenges these individuals faced in managing their health conditions and in losing physical function.

Making decisions together. Care recipients and caregivers worked together to make treatment decisions that were satisfactory to both parties. The caregiver made sure that the individual's preferences for care were recognized, and the care recipient made sure that the caregiver's needs were taken into account.

Relationships with conflicts included these behaviors:

Disagreement about caregivers' level of involvement. Some care recipients felt that their caregivers were too involved. In visits with healthcare providers, the individuals felt that, with their caregivers present, their own voices were not getting heard. Caregivers felt that their involvement was necessary to impart accurate information when the care recipients lacked English-language skills or intentionally withheld information from healthcare providers.

Disagreement about one another's competency to perform disease management tasks. Some care recipients did not trust their caregivers to administer medications, although caregivers felt equipped to perform this task. Caregivers in these situations also were skeptical of care recipients' abilities to carry out treatment regimens, manage medications, or communicate adequately with healthcare providers, even though care recipients felt able to perform these activities without assistance.

Under-appreciation. In "conflict" relationships, care recipients often felt that the caregiver had unrealistic expectations of their abilities to manage their health conditions. Caregivers described their roles as being "the mother of a toddler" or as an "unpaid slave," stating that the person being cared for did not fully recognize the stress associated with caregiving.

Disagreement over decision-making and disease management. Some care recipients and caregivers disagreed over decisions about healthcare, including rehabilitation and the day-to-day management of a care recipient's health conditions (e.g., diet, exercise, number of blood draws, and the use of assistive devices).

While older adults with multiple chronic illnesses and their family caregivers perform a universal set of disease management activities, their preferences for accepting or providing assistance with those activities are highly personal. The researchers said their findings support a family-centered approach to working with these individuals and their caregivers.

Bile acids -- gut compounds that aid in the digestion of dietary fats -- reduce the desire for cocaine, according to a new study by researchers at Vanderbilt University Medical Center and the University of Alabama at Birmingham.

The findings, published in the journal PLOS Biology, suggest that targeting bile acid signaling in the brain may be a novel way to treat cocaine abuse.

Vanderbilt investigators Charles (Robb) Flynn, PhD, associate professor of Surgery, and Naji Abumrad, MD, John L. Sawyers Professor of Surgical Sciences, have long studied the metabolic changes associated with bariatric surgery for weight loss. Surgical patients experience dramatic changes in glucose regulation and in taste preferences and food cravings while they are still in the recovery room, Flynn said.

"These surgeries are doing something more than we understand. We wondered if elevated serum bile acids, a hallmark of bariatric surgery, were affecting the reward centers of the brain to blunt the pleasure of eating high-fat foods," he said.

If the surgery did affect the brain's reward centers, he added, "how might it impact the rewarding properties of drugs of abuse?"

The most commonly performed bariatric surgery -- Roux-en-Y gastric bypass -- restricts the size of the stomach and alters the path of food through the digestive tract. It also changes the point where bile acids enter the small intestine, from the usual upper part of the small intestine to a site near the end. The change increases circulating levels of bile acids in the body.

To explore the effects of bariatric surgery and elevated bile acids, Flynn's group developed a simpler surgical procedure in mice called bile diversion, in which the gall bladder is surgically connected to the end of the small intestine. Bile diversion in an obese mouse produces all of the beneficial effects of bariatric surgery: weight loss, reduced food intake and improved oral glucose tolerance, Flynn said.

With colleague Aurelio Galli, PhD, a former Vanderbilt faculty member who is now at the University of Alabama at Birmingham, the investigators found that bile diversion surgery in normal-weight mice reduced cocaine-induced increases in brain dopamine release and reduced cocaine-associated behaviors.

The researchers tested the effects of a synthetic bile acid drug called obeticholic acid (OCA), which is clinically approved to treat the chronic liver disease primary biliary cholangitis. In mice without surgery, OCA administration mimicked the effects of bile diversion surgery in reducing cocaine-associated behaviors. The investigators further demonstrated that the bile acid receptor TGR5 mediates the effects of elevated bile acids and OCA in the nucleus accumbens, a brain region that plays a central role in reward circuitry.

The study is the first to demonstrate a central nervous system role for bile acids in altering reward-related behaviors, and it opens the possibility of treating drug abuse in new ways.

"Will bile acids cure cocaine addiction in humans? We don't know, but our research certainly suggests that bariatric surgery or consumption of bile acids may have beneficial effects," Flynn said.

"OCA is already clinically approved, so it might be possible to move quickly to clinical trials of its efficacy in treating addiction."

NEW YORK, August 30, 2018 - Venomous reptiles, bugs and marine life have notorious reputations as dangerous, sometimes life-threatening creatures. But in a paper in the current issue of Science, first author Mandë Holford, an associate professor of chemistry and biochemistry at The Graduate Center of The City University of New York (GC/CUNY) and Hunter College, details how technology and a growing understanding of the evolution of venoms are pointing the way toward entirely new classes of drugs capable of treating diabetes, autoimmune diseases, chronic pain, and other conditions.

According to Holford and her colleagues, venomous species account for more than 15 percent of the Earth's documented biodiversity, and they can be found in virtually all marine and terrestrial habitats. Still, researchers have studied very few venoms because until recently they lacked the appropriate technology for analyzing the tiny amounts of venom that can be extracted from these mostly small species. But innovations in omics (technologies that map the roles, relationships, and actions of an organism's molecular structure) are allowing researchers to uncover evolutionary changes and diversification among specific venomous species that could prove useful in developing new drugs capable of precisely targeting and binding to molecules that are active in certain human diseases.

"Knowing more about the evolutionary history of venomous species can help us make more targeted decisions about the potential use of venom compounds in treating illnesses," said Holford. "New environments, the development of venom resistance in its prey, and other factors can cause a species to evolve in order to survive. These changes can produce novel compounds -- some of which may prove extremely useful in drug development."

To date, only six Food and Drug Administration-approved, venom-derived drugs have been developed as a result of modern-day research, but Holford and her colleagues believe greater investment in venom research could yield therapies for currently untreatable diseases as well as improved therapeutic options.

Potential drug advances include therapeutic peptides derived from the venomous sea anemone, which researchers believe could treat autoimmune diseases; therapeutic neurotoxins derived from the Conus magus, which scientists think could provide non-addictive treatment of chronic pain; chlorotoxin from the deathstalker scorpion, which could be the basis for a surgical tumor-imaging technique; and spider toxins, which could yield ecofriendly insecticides.

Holford and her follow authors conclude that an evolution-informed perspective will help focus venom research so that it can leverage the extraordinary biochemical warfare created by nature to yield transformative therapeutics and bio-insecticides.