Duke Research Blog

Following the people and events that make up the research community at Duke.

Category: Medicine (Page 1 of 14)

Smart Phones Are the New Windows to the Soul

It’s one of those things that seems so simple and elegant that you’re left asking yourself, “Geez, why didn’t I think of that?”

Say you were trying to help people lose weight, prep for a surgery or take their meds every day. They’re probably holding a smartphone in at least one of their hands — all you need to do is enlist that ever-present device they’re staring at to bug them!

So, for example, have the health app send a robo-text twice a day to check in: “Did you weigh yourself?” Set up a group chat where their friends all know what they’re trying to accomplish: “We’re running today at 5, right?”

This is a screenshot of a Pattern Health app for pre-operative patients.

It’s even possible to make them pinky-swear a promise to their phone that they will do something positive toward the goal, like walking or skipping desert that day. And if they don’t? The app has their permission to lock them out of all their apps for a period of time.

Seriously, people agree to this and it works.

Two app developers on this frontier of personalized, portable “mHealth” told a lunchtime session  sponsored by the Duke Mobile App Gateway on Thursday that patients not only willingly play along with these behavioral modification apps, their behaviors change for the better.

The idea of using phones for health behavior came to pediatric hematologist Nirmish Shah MD one day while he attempted to talk to a 16-year-old sickle cell disease patient as she snapped selfies of herself with the doctor. Her mom and toddler sister nearby both had their noses to screens as well. “I need to change how I do this,” Shah thought to himself.

Pediatric hematologist Nirmish Shah MD

Pediatric hematologist Nirmish Shah MD is director of Duke’s sickle cell transition program.

Twenty health apps later, he’s running phase II clinical trials of phone-based interventions for young sickle cell patients that encourage them to stay on their medication schedule and ask them often about their pain levels.

One tactic that seems to work pretty well is to ask his patients to send in selfie videos as they take their meds each day. The catch? The female patients send a minute or so of chatty footage a day. The teenage boys average 13 seconds, and they’re grumpy about it.

Clearly, different activities may be needed for different patient populations, Shah said.

While it’s still early days for these approaches, we do have a lot of behavioral science on what could help, said Aline Holzwarth, a principal of the Center for Advanced Hindsight and head of behavioral science for a Durham health app startup called Pattern Health.

Aline Gruneisen Holzwarth

Aline Holzwarth is a principal in the Center for Advanced Hindsight.

“It’s not enough to simply inform people to eat better,” Holzwarth said. The app has to secure a commitment from the user, make them set small goals and then ask how they did, enlist the help of social pressures, and then dole out rewards and punishments as needed.

Pattern Health’s app says “You need to do this, please pick a time when you will.” Followed by a reward or a consequence.

Thursday’s session, “Using Behavioral Science to Drive Digital Health Engagement and Outcomes, was the penultimate session of the annual Duke Digital Health Week. Except for the Hurricane Florence washout on Monday, the week  has been a tremendous success this year, said Katie McMillan, the associate director of the App Gateway.

Combatting the Opioid Epidemic

The opioid epidemic needs to be combatted in and out of the clinic.

In the U.S. 115 people die from opioids every day. The number of opioid overdoses increased fivefold from 1999 to 2016. While increased funding for resources like Narcan has helped — the opioid overdose-reversing drug now carried by emergency responders in cities throughout the country — changes to standard healthcare practices are still sorely needed.

Ashwin A Patkar, MD, medical director of the Duke Addictions Program, spoke to the Duke Center on Addiction and Behavior Change about how opioid addiction is treated.

The weaknesses of the current treatment standards first appear in diagnosis. Heroin and cocaine are currently being contaminated by distributors with fentanyl, an opioid that is 25 to 50 times more potent than heroin and cheaper than either of these drugs. Despite fentanyl’s prevalence in these street drugs, the standard form and interview for addiction patients does not include asking about or testing for the substance.

Patkar has found that 30 percent of opioid addiction patients have fentanyl in their urine and do not disclose it to the doctor. Rather than resulting from the patients’ dishonesty, Patkar believes, in most cases, patients are taking fentanyl without knowing that the drugs they are taking are contaminated.

Because of its potency, fentanyl causes overdoses that may require more Narcan than a standard heroin overdose. Understanding the prevalence of Narcan in patients is vital both for public health and educating patients so they can be adequately prepared.

Patkar also pointed out that, despite a lot of research supporting medication-assisted therapy, only 21 percent of addiction treatment facilities in the U.S. offer this type of treatment. Instead, most facilities rely on detoxification, which has high rates of relapse (greater than 85 percent within a year after detox) and comes with its own drawbacks. Detox lowers the patient’s tolerance to the drug, but care providers often neglect to tell the patients this, resulting in a rate of overdose that is three times higher than before detox.

Another common treatment for opioid addiction involves using methadone, a controlled substance that helps alleviate symptoms from opioid withdrawal. Because retention rate is high and cost of production is low, methadone poses a strong financial incentive. However, methadone itself is addictive, and overdose is possible.

Patkar points to a resource developed by Julie Bruneau as a reference for the Canadian standard of care for opioid abuse disorder. Rather than recommending detox or methadone as a first line of treatment, Bruneau and her team recommend buprenorphine , and naltrexone as a medication to support abstinence after treatment with buprenorphine.

Buprenorphine is a drug with a similar function as methadone, but with better and safer clinical outcomes. Buprenorphine does not create the same euphoric effect as methadone, and rates of overdose are six times less than in those prescribed methadone.

In addition to prescribing the right medicine, clinicians need to encourage patients to stick with treatment longer. Despite buprenorphine having good outcomes, patients who stop taking it after only 4 to 12 weeks, even with tapering directed by a doctor, exhibit only an 18 percent rate of successful abstinence.

Patkar closed his talk by reminding the audience that opioid addiction is a brain disease. In order to see a real change in the number of people dying from opioids, we need to focus on treating addiction as a disease; no one would question extended medication-based treatment of diseases like diabetes or heart disease, and the same should be said about addiction. Healthcare providers have a responsibility to treat addiction based on available research and best practices, and patients with opioid addiction deserve a standard of care the same as anyone else.

Post by undergraduate blogger Sarah Haurin

Post by undergraduate blogger Sarah Haurin

Medicine, Research and HIV

Duke senior Jesse Mangold has had an interest in the intersection of medicine and research since high school. While he took electives in a program called “Science, Medicine, and Research,” it wasn’t until the summer after his first year at Duke that he got to participate in research.

As a member of the inaugural class of Huang fellows, Mangold worked in the lab of Duke assistant professor Christina Meade on the compounding effect of HIV and marijuana use on cognitive abilities like memory and learning.

The following summer, Mangold traveled to Honduras with a group of students to help with collecting data and also meeting the overwhelming need for eye care. Mangold and the other students traveled to schools, administered visual exams, and provided free glasses to the children who needed them. Additionally, the students contributed to a growing research project, and for their part, put together an award-winning poster.

Mangold’s (top right) work in Honduras helped provide countless children with the eye care they so sorely needed.

Returning to school as a junior, Mangold wanted to focus on his greatest research interest: the molecular mechanisms of human immunodeficiency virus (HIV). Mangold found a home in the Permar lab, which investigates mechanisms of mother-to-child transmission of viruses including HIV, Zika, and Cytomegalovirus (CMV).

From co-authoring a book chapter to learning laboratory techniques, he was given “the opportunity to fail, but that was important, because I would learn and come back the next week and fail a little bit less,” Mangold said.

In the absence of any treatment, mothers who are HIV positive transmit the virus to their infants only 30 to 40 percent of the time, suggesting a component of the maternal immune system that provides at least partial protection against transmission.

The immune system functions through the activity of antibodies, or proteins that bind to specific receptors on a microbe and neutralize the threat they pose. The key to an effective HIV vaccine is identifying the most common receptors on the envelope of the virus and engineering a vaccine that can interact with any one of these receptors.

This human T cell (blue) is under attack by HIV (yellow), the virus that causes AIDS. Credit: Seth Pincus, Elizabeth Fischer and Austin Athman, National Institute of Allergy and Infectious Diseases, National Institutes of Health

This human T cell (blue) is under attack by HIV (yellow), the virus that causes AIDS. Credit: Seth Pincus, Elizabeth Fischer and Austin Athman, National Institute of Allergy and Infectious Diseases, National Institutes of Health

Mangold is working with Duke postdoctoral associate Ashley Nelson, Ph.D., to understand the immune response conferred on the infants of HIV positive mothers. To do this, they are using a rhesus macaque model. In order to most closely resemble the disease path as it would progress in humans, they are using a virus called SHIV, which is engineered to have the internal structure of simian immunodeficiency virus (SIV) and the viral envelope of HIV; SHIV can thus serve to naturally infect the macaques but provide insight into antibody response that can be generalized to humans.

The study involves infecting 12 female monkeys with the virus, waiting 12 weeks for the infection to proceed, and treating the monkeys with antiretroviral therapy (ART), which is currently the most effective treatment for HIV. Following the treatment, the level of virus in the blood, or viral load, will drop to undetectable levels. After an additional 12 weeks of treatment and three doses of either a candidate HIV vaccine or a placebo, treatment will be stopped. This design is meant to mirror the gold-standard of treatment for women who are HIV-positive and pregnant.

At this point, because the treatment and vaccine are imperfect, some virus will have survived and will “rebound,” or replicate fast and repopulate the blood. The key to this research is to sequence the virus at this stage, to identify the characteristics of the surviving virus that withstood the best available treatment. This surviving virus is also what is passed from mothers on antiretroviral therapy to their infants, so understanding its properties is vital for preventing mother-to-child transmission.

As a Huang fellow, Mangold had the opportunity to present his research on the compounding effect of HIV and marijuana on cognitive function.

Mangold’s role is looking into the difference in viral diversity before treatment commences and after rebound. This research will prove fundamental in engineering better and more effective treatments.

In addition to working with HIV, Mangold will be working on a project looking into a virus that doesn’t receive the same level of attention as HIV: Cytomegalovirus. CMV is the leading congenital cause of hearing loss, and mother-to-child transmission plays an important role in the transmission of this devastating virus.

Mangold and his mentor, pediatric resident Tiziana Coppola, M.D., are authoring a paper that reviews existing literature on CMV to look for a link between the prevalence of CMV in women of child-bearing age and whether this prevalence is predictive of the number of children suffer CMV-related hearing loss. With this study, Mangold and Coppola are hoping to identify if there is a component of the maternal immune system that confers some immunity to the child, which can then be targeted for vaccine development.

After graduation, Mangold will continue his research in the Permar lab during a gap year while applying to MD/PhD programs. He hopes to continue studying at the intersection of medicine and research in the HIV vaccine field.

Post by undergraduate blogger Sarah Haurin

Post by undergraduate blogger Sarah Haurin

 

Teaching a Machine to Spot a Crystal

A collection of iridescent crystals grown in space

Not all protein crystals exhibit the colorful iridescence of these crystals grown in space. But no matter their looks, all are important to scientists. Credit: NASA Marshall Space Flight Center (NASA-MSFC).

Protein crystals don’t usually display the glitz and glam of gemstones. But no matter their looks, each and every one is precious to scientists.

Patrick Charbonneau, a professor of chemistry and physics at Duke, along with a worldwide group of scientists, teamed up with researchers at Google Brain to use state-of-the-art machine learning algorithms to spot these rare and valuable crystals. Their work could accelerate drug discovery by making it easier for researchers to map the structures of proteins.

“Every time you miss a protein crystal, because they are so rare, you risk missing on an important biomedical discovery,” Charbonneau said.

Knowing the structure of proteins is key to understanding their function and possibly designing drugs that work with their specific shapes. But the traditional approach to determining these structures, called X-ray crystallography, requires that proteins be crystallized.

Crystallizing proteins is hard — really hard. Unlike the simple atoms and molecules that make up common crystals like salt and sugar, these big, bulky molecules, which can contain tens of thousands of atoms each, struggle to arrange themselves into the ordered arrays that form the basis of crystals.

“What allows an object like a protein to self-assemble into something like a crystal is a bit like magic,” Charbonneau said.

Even after decades of practice, scientists have to rely in part on trial and error to obtain protein crystals. After isolating a protein, they mix it with hundreds of different types of liquid solutions, hoping to find the right recipe that coaxes them to crystallize. They then look at droplets of each mixture under a microscope, hoping to spot the smallest speck of a growing crystal.

“You have to manually say, there is a crystal there, there is none there, there is one there, and usually it is none, none, none,” Charbonneau said. “Not only is it expensive to pay people to do this, but also people fail. They get tired and they get sloppy, and it detracts from their other work.”

Three microscope images of protein crystallization solutions

The machine learning software searches for points and edges (left) to identify crystals in images of droplets of solution. It can also identify when non-crystalline solids have formed (middle) and when no solids have formed (right).

Charbonneau thought perhaps deep learning software, which is now capable of recognizing individual faces in photographs even when they are blurry or caught from the side, should also be able to identify the points and edges that make up a crystal in solution.

Scientists from both academia and industry came together to collect half a million images of protein crystallization experiments into a database called MARCO. The data specify which of these protein cocktails led to crystallization, based on human evaluation.

The team then worked with a group led by Vincent Vanhoucke from Google Brain to apply the latest in artificial intelligence to help identify crystals in the images.

After “training” the deep learning software on a subset of the data, they unleashed it on the full database. The A.I. was able to accurately identify crystals about 95 percent of the time. Estimates show that humans spot crystals correctly only 85 percent of the time.

“And it does remarkably better than humans,” Charbonneau said. “We were a little surprised because most A.I. algorithms are made to recognize cats or dogs, not necessarily geometrical features like the edge of a crystal.”

Other teams of researchers have already asked to use the A.I. model and the MARCO dataset to train their own machine learning algorithms to recognize crystals in protein crystallization experiments, Charbonneau said. These advances should allow researchers to focus more time on biomedical discoveries instead of squinting at samples.

Charbonneau plans to use the data to understand how exactly proteins self-assemble into crystals, so that researchers rely less on chance to get this “magic” to happen.

“We are trying to use this data to see if we can get more insight into the physical chemistry of self-assembly of proteins,” Charbonneau said.

CITATION: “Classification of crystallization outcomes using deep convolutional neural networks,” Andrew E. Bruno, et al. PLOS ONE, June 20, 2018. DOI: 10.1371/journal.pone.0198883

 

Post by Kara Manke

Quantifying Sleepiness and How It Relates to Depression

Sleep disturbance is a significant issue for many individuals with depressive illnesses. While most individuals deal with an inability to sleep, or insomnia, about 20-30% of depressed patients report the opposite problem – hypersomnia, or excessive sleep duration.

David Plante’s work investigates the relationship between depressive disorders and hypersomnolence. Photo courtesy of sleepfoundation.org

Patients who experience hypersomnolence report excessive daytime sleepiness (EDS) and often seem to be sleep-deprived, making the condition difficult to identify and poorly researched.

David Plante’s research focuses on a neglected type of sleep disturbance: hypersomnolence.

David T. Plante, MD, of the University of Wisconsin School of Medicine and Public Health, studies the significance of hypersomnolence in depression. He said the condition is resistant to treatment, often persisting even after depression has been treated, and its role in increasing risk of depression in previously healthy individuals needs to be examined.

One problem in studying daytime sleepiness is quantifying it. Subjective measures include the Epworth sleepiness scale, a quick self-report of how likely you are to fall asleep in a variety of situations. Objective scales are often involved processes, such as the Multiple Sleep Latency Test (MSLT), which requires an individual to attempt to take 4-5 naps, each 2 hours apart, in a lab while EEG records brain activity.

The MSLT measures how long it takes a person to fall asleep. Individuals with hypersomnolence will fall asleep faster than other patients, but determining a cutoff for what constitutes healthy and what qualifies as hypersomnolence has made the test an inexact measure. Typical cutoffs of 5-8 minutes provide a decent measure, but further research has cast doubt on this test’s value in studying depression.

The Wisconsin Sleep Cohort Study is an ongoing project begun in 1988 that follows state employees and includes a sleep study every four years. From this study, Plante has found an interesting and seemingly paradoxical relationship: while an increase in subjective measures of sleepiness is associated with increased likelihood of depression, objective measures like the MSLT associate depression with less sleepiness. Plante argues that this paradoxical relationship does not represent an inability for individuals to report their own sleepiness, but rather reflects the limitations of the MSLT.

Plante proposed several promising candidates for quantitative measures of excessive daytime sleepiness. One candidate, which is already a tool for studying sleep deprivation, is a ‘psychomotor vigilance task,’ where lapses in reaction time correlate with daytime sleepiness. Another method involves infrared measurements of the dilation of the pupil. Pupils dilate when a person is sleepy, so this somatic reaction could be useful.

High density EEG allowed Plante to identify the role of disturbed slow wave sleep in hypersomnolence.

Another area of interest for Plante is the signs of depressive sleepiness in the brain. Using high density EEG, which covers the whole head of the subject, Plante found that individuals with hypersomnolence experience less of the sleep cycle most associated with restoration, known as slow wave sleep. He identified a potential brain circuitry associated with sleepiness, but emphasized a need for methods like transcranial magnetic stimulation to get a better picture of the relationship between this circuitry and observed sleepiness.

By Sarah Haurin

ECT: Shockingly Safe and Effective

Husain is interested in putting to rest misconceptions about the safety and efficacy of ECT.

Few treatments have proven as controversial and effective as electroconvulsive therapy (ECT), or ‘shock therapy’ in common parlance.

Hippocrates himself saw the therapeutic benefits of inducing seizures in patients with mental illness, observing that convulsions caused by malaria helped attenuate symptoms of mental illness. However, depictions of ECT as a form of medical abuse, as in the infamous scene from One Flew Over the Cuckoo’s Nest, have prevented ECT from becoming a first-line psychiatric treatment.

The Duke Hospital Psychiatry program recently welcomed back Duke Medical School alumnus Mustafa Husain to deliver the 2018 Ewald “Bud” Busse Memorial Lecture, which is held to commemorate a Duke doctor who pioneered the field of geriatric psychiatry.

Husain, from the University of Texas Southwestern, delivered a comprehensive lecture on neuromodulation, a term for the emerging subspecialty of psychiatric medicine that focuses on physiological treatments that are not medication.

The image most people have of ECT is probably the gruesome depiction seen in “One Flew Over the Cuckoo’s Nest.”

Husain began his lecture by stating that ECT is one of the most effective treatments for psychiatric illness. While medication and therapy are helpful for many people with depression, a considerable proportion of patients’ depression can be categorized as “treatment resistant depression” (TRD). In one of the largest controlled experiments of ECT, Husain and colleagues showed that 82 percent of TRD patients treated with ECT were remitted. While this remission rate is impressive, the rate at which remitted individuals experience a relapse into symptoms is also substantial – over 50% of remitted individuals will experience relapse.

Husain’s study continued to test whether a continuation of ECT would be a potentially successful therapy to prevent relapse in the first six months after acute ECT. He found that continuation of ECT worked as well as the current best combination of drugs used.

From this study, Husain made an interesting observation – the people who were doing best in the 6 months after ECT were elderly patients. He then set out to study the best form of treatment for these depressed elderly patients.

Typically, ECT involves stimulation of both sides of the brain (bilateral), but this treatment is associated with adverse cognitive effects like memory loss. Using right unilateral ECT effectively decreased cognitive side effects while maintaining an appreciable remission rate.

After the initial treatment, patients were again assigned to either receive continued drug treatment or continued ECT. In contrast to the previous study, however, the treatment for continued ECT was designed based on the individual patients’ ratings from a commonly used depression scaling system.

The results of this study show the potential that ECT has in becoming a more common treatment for major depressive disorder: maintenance ECT showed a lower relapse rate than drug treatment following initial ECT. If psychiatrists become more flexible in their prescription of ECT, adjusting the treatment plan to accommodate the changing needs of the patients, a disorder that is exceedingly difficult to treat could become more manageable.

In addition to discussing ECT, Husain shared his research into other methods of neuromodulation, including Magnetic Seizure Therapy (MST). MST uses magnetic fields to induce seizures in a more localized region of the brain than available via ECT.

Importantly, MST does not cause the cognitive deficits observed in patients who receive ECT. Husain’s preliminary investigation found that a treatment course relying on MST was comparable in efficacy to ECT. While further research is needed, Husain is hopeful in the possibilities that interventional psychiatry can provide for severely depressed patients.

By Sarah Haurin 

First Population Health Conference Shares Energy, Examples

Logo: Population Health at Duke‘Population Health’ is the basis of a new department in the School of Medicine, a byword for a lot of new activity across campus , and on Tuesday the subject of a half-day symposium that attempted to bring all this energy together.

For now, population health means a lot of different things to a lot of different people.

The half-day symposium drew an overflow crowd of faculty and staff. (photo – Colin Huth)

“We’re still struggling with a good definition of what population health is,” said keynote speaker Clay Johnston, MD, PhD, dean of the new Dell School of Medicine in Austin, Texas. Smoking cessation programs are something most everyone would agree is taking care of the population outside of the clinic. But improved water quality? Where does that fit?

“We have an intense focus on doctors and their tools,” Johnston said. Our healthcare system is optimized for maximum efficiency in fee-for-service care, that is, getting the most revenue out of the most transactions. “But most of health is outside the clinic,” Johnston said.

Perhaps as a result, the United States pays much more for health care, but lives less well, he said. “We are noticeably off the curve,” when compared to health care costs and outcomes in other countries.

This graphic from a handout shared at the conference shows how population health spans the entire university.

This graphic from a handout shared at the conference shows how population health spans the entire university.

As an example of what might be achieved in population health with some re-thinking and a shift in resources, the Dell School went after the issue of joint pain with input from their engineering and business schools. Rather than diagnosing people toward an orthopedic surgery – for which there was a waitlist of about 14 months – their system worked with patients on alternatives, such as weight loss, physical therapy and behavioral changes before surgery. The 14-month backlog was gone in just three months. Surgeries still happen, of course, but not if they can be comfortably delayed or avoided.

“Payment for prevention needs serious work,” Johnston said. “You need to get people to buy into it,” but in diabetes or depression for example, employers should stand to gain a lot from having healthier employees who miss fewer days, he said.

Health Affairs Chancellor Eugene Washington commented several times, calling the discussion “very interesting and very valuable.” (photo -Colin Huth)

Other examples flowed freely the rest of the afternoon. Duke is testing virtual ‘telemedicine’ appointments versus office visits. Evidence-based prenatal care is being applied to try to avoid expensive neonatal ICU care. Primary care and Emergency Department physicians are being equipped with an app that helps them steer sickle cell patients to appropriate care resources so that they might avoid expensive ED visits.

Family practitioner Eugenie Komives, MD, is part of a team using artificial intelligence and machine learning to try to predict which patients are most likely to be hospitalized in the next six months. That prediction, in turn, can guide primary care physicians and care managers to pay special attention to these patients to help them avoid the hospital. The system is constantly being evaluated, she added. “We don’t want to be doing this if it doesn’t work.”

Community health measures like walkability and grocery stores are being mapped for Durham County on a site called Durham Neighborhood Compass, said Michelle Lyn, MBA, chief of the division of community health. The aim is not only to see where improvements can be made, but to democratize population health information and put it in peoples’ hands. “(Community members) will have ideas we never could have thought of,” Lyn said. “We will be able to see change across our neighborhoods and community.”

Patient input is key to population health, agreed several speakers. “I don’t think we’ve heard them enough,” said Paula Tanabe, PhD, an associate professor of nursing and medicine who studies pain and sickle cell disease.  “We need a bigger patient voice.”

Health Affairs Chancellor and Duke Health CEO Eugene Washington, MD, has made population health one of the themes of his leadership. “We really take seriously this notion of shaping the future of population health,” he said in his introductory remarks. “When I think of the future, I think about how well-positioned we are to have impact on the lives of the community we serve.”

Lesley Curtis, PhD, chair of the newly formed Department of Population Health Sciences in the School of Medicine, said Duke is creating an environment where this kind of work can happen.

“I, as an organizer of this, didn’t know about half of these projects today!” Curtis said. “There’s so much going on at an organic level that the challenge to us is to identify what’s going on and figure out how to go forward at scale.”

Post by Karl Leif Bates

Obesity: Do Your Cells Have a Sweet Tooth?

Obesity is a global public health crisis that has doubled since 1980. That is why Damaris N. Lorenzo, a professor of  Cell Biology and Physiology at UNC-Chapel Hill, has devoted her research to this topic.

Specifically, she examines the role of ankyrin-B variants in metabolism. Ankyrins play a role in the movement of substances such as ions into and out of the cell. One of the ways that ankyrins affect this movement is through the glucose transporter protein GLUT4 which is present in the heart, skeletal muscles, and insulin-responsive tissues. GLUT4 plays a large role in glucose levels throughout the entire body.

Through her research, Lorenzo discovered that with modern life spans and high calorie diets, ankyrin-B variants can be a risk factor for metabolic disease. She presented her work for the Duke Developmental & Stem Cell Biology department on March 7th.

Prevalence of Self-Reported Obesity Among U.S. Adults by State, 2016

GLUT4 helps remove glucose from the body’s circulation by moving it into cells. The more GLUT4, the more sugar cells absorb.

Ankyrin-B’s role in regulating GLUT4 therefore proves really important for overall health. Through experiments on mice, Lorenzo discovered that mice manipulated to have ankyrin-B mutations also had high levels of cell surface GLUT4. This led to increased uptake of glucose into cells. Ankyrin-B therefore regulates how quickly glucose enters adipocytes, cells that store fat. These ankyrin-B deficient mice end up with adipocytes that have larger lipid droplets, which are fatty acids.

Lorenzo was able to conclude that ankyrin-B deficiency leads to age-dependent obesity in mutant mice. Age-dependent because young ankyrin-B mutant mice with high fat diets are actually more likely to be affected by this change.

Obese mouse versus a regular mouse

Ankyrin-B has only recently been recognized as part of GLUT4 movement into the cell. As cell sizes grow through increased glucose uptake, not only does the risk of obesity rise but also inflammation is triggered and metabolism becomes impaired, leading to overall poor health.

With obesity becoming a greater problem due to increased calorie consumption, poor dietary habits, physical inactivity, environmental and life stressors, medical conditions, and drug treatments, understanding factors inside of the body can help. Lorenzo seeks to discover how ankyrin-B protein might play a role in the amount of sugar our cells internalize.

Post by Lydia Goff

MRI Tags Stick to Molecules with Chemical “Velcro®”

An extremely close-up view of Velcro

In the new technique, MRI chemical tags attach to a target molecule and nothing else – kind of like how Velcro only sticks to itself. Credit: tanakawho, via Flickr.

Imagine attaching a beacon to a drug molecule and following its journey through our winding innards, tracking just where and how it interacts with the chemicals in our bodies to help treat illnesses.

Duke scientists may be closer to doing just that. They have developed a chemical tag that can be attached to molecules to make them light up under magnetic resonance imaging (MRI).

This tag or “lightbulb” changes its frequency when the molecule interacts with another molecule, potentially allowing researchers to both locate the molecule in the body and see how it is metabolized.

“MRI methods are very sensitive to small changes in the chemical structure, so you can actually use these tags to directly image chemical transformations,” said Thomas Theis, an assistant research professor in the chemistry department at Duke.

Chemical tags that light up under MRI are not new. In 2016, the Duke team of Warren S. Warren’s lab and Qiu Wang’s lab created molecular lightbulbs for MRI that burn brighter and longer than any previously discovered.

A photo of graduate students Junu Bae and Zijian Zhou in front of a bookshelf.

Junu Bae and Zijian Zhou, the co-first authors of the paper. Credit: Qiu Wang, Duke University.

In a study published March 9 in Science Advances, the researchers report a new method for attaching tags to molecules, allowing them to tag molecules indirectly to a broader scope of molecules than they could before.

“The tags are like lightbulbs covered in Velcro,” said Junu Bae, a graduate student in Qiu Wang’s lab at Duke. “We attach the other side of the Velcro to the target molecule, and once they find each other they stick.”

This reaction is what researchers call bioorthogonal, which means that the tag will only stick to the molecular target and won’t react with any other molecules.

And the reaction was designed with another important feature in mind — it generates a rare form of nitrogen gas that also lights up under MRI.

“One could dream up a lot of potential applications for the nitrogen gas, but one that we have been thinking about is lung imaging,” Theis said.

Currently the best way to image the lungs is with xenon gas, but this method has the downside of putting patients to sleep. “Nitrogen gas would be perfectly safe to inhale because it is what you inhale in the air anyways,” Theis said.

A stylized chemical diagram of the hyperpolarization process

In the new technique, a type of molecule called a tetrazine is hyperpolarized, making it “light up” under MRI (illustrated on the left). It is then tagged to a target molecule through a what is called a bioorthogonal reaction. The reaction also generates a rare form of nitrogen gas that can be spotted under MRI (illustrated on the right). Credit: Junu Bae and Seoyoung Cho, Duke University.

Other applications could include watching how air flows through porous materials or studying the nitrogen fixation process in plants.

One downside to the new tags is that they don’t shine as long or as brightly as other MRI molecular lightbulbs, said Zijian Zhou, a graduate student in  Warren’s lab at Duke.

The team is tinkering with the formula for polarizing, or lighting up, the molecule tags to increase their lifetime and brilliance, and to make them more compatible with chemical conditions in the human body.

“We are now developing new techniques and new procedures which may be helpful for driving the polarization levels even higher, so we can have even better signal for these applications,” Zhou said.

15N4-1,2,4,5-tetrazines as potential molecular tags: Integrating bioorthogonal chemistry with hyperpolarization and unearthing para-N2,” Junu Bae, Zijian Zhou, Thomas Theis, Warren S. Warren and Qiu Wang. Science Advances, March 9, 2018. DOI: 10.1126/sciadv.aar2978

Post by Kara Manke

How A Zebrafish’s Squiggly Cartilage Transforms into a Strong Spine

A column of green cartilage cells divides into an alternating pattern of green cartilage and red vertebra

Our spines begin as a flexible column called the notochord. Over time, cells on the notochord surface divide into alternating segments that go on to form cartilage and vertebrae.

In the womb, our strong spines start as nothing more than a rope of rubbery tissue. As our bodies develop, this flexible cord, called the notochord, morphs into a column of bone and cartilage sturdy enough to hold up our heavy upper bodies.

Graduate student Susan Wopat and her colleagues in Michel Bagnat’s lab at Duke are studying the notochords of the humble zebrafish to learn how this cartilage-like rope grows into a mature spine.

In a new paper, they detail the cellular messaging that directs this transformation.

It all comes down to Notch receptors on the notochord surface, they found. Notch receptors are a special type of protein that sits astride cell membranes. When two cells touch, these Notch receptors link up, forming channels that allow messages to rapidly travel between large groups of cells.

Notch receptors divide the outer notochord cells into two alternating groups – one group is told to grow into bone, while the other is told to grow into cartilage. Over time, bone starts to form on the surface of the notochord and works its way inward, eventually forming mature vertebrae.

X-ray images of four zebrafish spines

Meddling with cellular signaling on the notochord surface caused zebrafish spines to develop deformities. The first and third image show healthy spines, and the second and fourth image show deformed spines.

When the team tinkered with the Notch signaling on the surface cells, they found that the spinal vertebrae came out deformed – too big, too small, or the wrong shape.

“These results demonstrate that the notochord plays a critical role in guiding spine development,” Wopat said. “Further investigation into these findings may help us better understand the origin of spinal defects in humans.”

Spine patterning is guided by segmentation of the notochord sheath,” Susan Wopat, Jennifer Bagwell, Kaelyn D. Sumigray, Amy L. Dickson, Leonie F. Huitema, Kenneth D. Poss, Stefan Schulte-Merker, Michel Bagnat. Cell, February 20, 2018. DOI: 10.1016/j.celrep.2018.01.084

Post by Kara Manke

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