Almost precisely a decade ago, a young Atlanta lawyer named Anna was returning to work, after being treated for an extraordinary sleep disorder. Her story has been told here at Emory and by national media outlets.
Fast forward a decade to Idiopathic Hypersomnia Awareness Week 2018 (September 3-9), organized by Hypersomnolence Australia. What this post deals with is essentially the correction of a date at the tail end of Anna’s story, but one with long-term implications Read more
Last week, Lab Land put out a Twitter poll, touching on the cognitive distortions that make it difficult to do high-quality science. Lots of people (almost 50) responded! Thank you!
We had to be vague about where all this came from, because it was before the publication of the underlying research paper. Ray Dingledine, in Emory’s Department of Pharmacology, asked us to do the Twitter poll first, to see what answers people would give. Dingledine’s Read more
Scientists at Winship Cancer Institute, Emory University have identified compounds that stop two elusive anticancer targets from working together. In addition to striking two birds with one stone, this research could expand the envelope of what is considered “druggable.”
Many of the proteins and genes that have critical roles in cancer cell growth and survival have been conventionally thought of as undruggable. That’s because they’re inside the cell and aren’t enzymes, for which chemists have well-developed sabotage strategies.
In a twist, the potential anticancer drugs described in Cancer Celldisable an interaction between a notorious cancer-driving protein, MDM2, and a RNA encoding a radiation-resistance factor, XIAP.
The compounds could be effective against several types of cancer, says senior author Muxiang Zhou, MD, professor of pediatrics (hematology/oncology) at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center.
In the paper, the compounds show activity against leukemia and neuroblastoma cells in culture and in mice, but a fraction of many other cancers, such as breast cancers (15 percent) and sarcoma (20 percent), show high levels of MDM2 and should be susceptible to them.
Drugs that interfere with bile acid recycling can prevent several aspects of NASH (nonalcoholic steatohepatitis) in mice fed a high-fat diet, scientists from Emory University School of Medicine and Children’s Healthcare of Atlanta have shown.
The findings suggest that these drugs, known as ASBT inhibitors, could be a viable clinical strategy to address NASH, an increasingly common liver disease. The results were published in Science Translational Medicine on September 21, 2016.
“By targeting a process that takes place in the intestine, we can improve liver function and reduce insulin resistance in a mouse model of NASH,” says senior author Saul Karpen, MD, PhD. “We can even get fat levels in the liver down to what we see in mice fed a regular diet. These are promising results that need additional confirmation in human clinical trials.”
Many people in developed countries have non-alcoholic fatty liver disease, an accumulation of fat in the liver that is linked to diet and obesity. Fatty liver disease confers an elevated risk of type II diabetes and heart disease. NASH is a more severe inflammation of the liver that can progress to cirrhosis, and is a rising indication for liver transplant. Besides diet and exercise, there are no medical treatments for NASH, which affects an estimated 2 to 5 percent of Americans. Read more
New research illustrates how “disease in a dish” stem cell technology can advance cardiology.
Scientists led by Chunhui Xu, PhD derived cardiac muscle cells from a teenaged boy with an inherited heart arrhythmia, and used them to study how his cells respond to drugs. They did this not through a cardiac biopsy, but by converting some of the boy’s skin cells into induced pluripotent stem cells, and then into cardiac muscle cells.
Xu, director of the Cardiomyocyte Stem Cell Lab in Emory’s Department of Pediatrics, says this approach has been helpful in the study of other inherited arrhythmias and cardiomyopathies (example: 2011 Nature paper on long QT syndrome). In addition, Xu says, human-derived cardiac muscle cells could be used for toxicology testing for new drugs, since the molecules that regulate human cardiac muscle cells functions are distinct from those in animal models.
In the patient whose cells are described in the paper, the drug flecainide could suppress arrhythmias that would otherwise appear during exercise. Electrocardiography from Preininger et al, Disease Models & Mechanisms (2016) via Creative Commons.
Arrhythmias in CPVT are almost exclusively brought on by activities that generate high levels of epinephrine, also known as adrenaline: heavy exertion, sports or emotional stress. Thus, affected individuals need to take medication regularly and usually should avoid competitive sports. The boy in the study also had an implanted cardiac defibrillator.
CPVT is generally treatable with beta-blockers, but about 25 percent of patients – including the boy in the study — are inadequately protected from arrhythmias by beta-blockers. Taking the drug flecainide, also used to treat atrial fibrillation, provides him an additional level of control.
Xu and her colleagues could duplicate those effects with his cardiac muscle cells in culture, by observing the ability of the drugs to suppress aberrant “calcium sparks.”
“We were able to recapitulate in a petri dish what we had seen in the patient,” says co-author Peter Fischbach, MD, chief academic officer at Children’s Healthcare of Atlanta’s Sibley Heart Center and associate professor of pediatrics at Emory University School of Medicine. “The hope is that in the future, we will be able to do that in reverse order.” Read more
Cardiac muscle cells derived from stem cells could eventually be used to treat heart diseases in children or adults, reshaping hearts with congenital defects or repairing damaged tissue.
Cardiomyocytes produced with the help of simulated microgravity. Red represents the cardiac muscle marker troponin, and green is cadherin, which helps cells stick to each other. Blue = cell nuclei. From Jha et al SciRep (2016).
Using the right growth factors and conditions, it is possible to direct pluripotent stem cells into becoming cardiac muscle cells, which form spheres that beat spontaneously. Researchers led by Chunhui Xu, PhD, director of the Cardiomyocyte Stem Cell Laboratory in Emory’s Department of Pediatrics, are figuring out how to grow lots of these muscle cells and keep them healthy and adaptable.
As part of this effort, Xu and her team discovered that growing stem cells under “simulated microgravity” for a few days stimulates the production of cardiac muscle cells, several times more effectively than regular conditions. The results were published on Friday, Aug. 5 in Scientific Reports. The first author of the paper is postdoctoral fellow Rajneesh Jha, PhD. Read more
Zika virus can infect and replicate in immune cells from the placenta, without killing them, scientists have discovered. The finding may explain how the virus can pass through the placenta of a pregnant woman, on its way to infect developing brain cells in her fetus.
Infected placental macrophages. Zika antigens visible in red. From Quicke et al (2016).
“Our results substantiate the limited evidence from pathology case reports,” says senior author Mehul Suthar, PhD, assistant professor of pediatrics at Emory University School of Medicine. “It was known that the virus was getting into the placenta. But little was known about where the virus was replicating and in what cell type.”
Scientists led by Suthar and Emory pediatric infectious disease specialist Rana Chakraborty, MD, found that Zika virus could infect placental macrophages, called Hofbauer cells, in cell culture. The virus could also infect another type of placental cell, called cytotrophoblasts, but only after a couple days delay and not as readily. Other researchers recently reported that syncytiotrophoblasts, a more differentiated type of placental cell than cytotrophoblasts, are resistant to Zika infection.
The cells for the experiments were derived from full-term placentae, obtained from healthy volunteers who delivered by Cesarean section. The level of viral replication varied markedly from donor to donor, which hints that some women’s placentae may be more susceptible to viral infection than others. Read more
Emory researchers have identified molecular mechanisms that regulate motivation and persistence in mice. Their findings could have implications for intervention in conditions characterized by behavioral inflexibility, such as drug abuse and depression.
Scientists showedÂ that by manipulating a particular growth factor in one region of the brain, they couldÂ tune up or down a mouseâ€™s tendency to persist in seeking a reward. In humans, this region of the brain is located just behind the eyes and is called the medial orbitofrontal cortex or mOFC.
â€œWhen we make decisions, we often need to gauge the value of a reward before we can see it — for example, will lunch at a certain restaurant be better than lunch at another, or worth the cost,â€ says Shannon Gourley, PhD, assistant professor of pediatrics and psychiatry at Emory University School of Medicine. â€œWe think the mOFC is important for calculating value, particularly when we have to imagine the reward, as opposed to having it right in front of us.â€
Being able to appropriately determine the value of a perceived reward is critical in goal-directed decision making, a component of drug-seeking and addiction-related behaviors. While scientists already suspected that the medial orbitofrontal cortex was important for this type of learning and decision-making, the specific genes and growth factors were not as well-understood.
The researchers focused on brain-derived neurotrophic factor (BDNF), a protein that supports the survival and growth of neurons in the brain. BDNF is known to play key roles in long-term potentiation and neuronal remodeling, both important in learning and memory tasks. Variations in the human gene that encodes BDNF have been linked with several psychiatric disorders.
Pediatric hepatologist Miriam Vos is starting a new study testing the effects of a low-sugar diet in children with NAFLD (non-alcoholic fatty liver disease).Â The study is supported by the Nutrition Science Initiative and conducted in a partnership with UCSD/Rady Childrenâ€™s Hospital, San Diego. See below for more on NUSI.
While there are no medications approved for NAFLD â€“ a healthy diet and exercise are the standard of care –Â plenty of drugs are under development, as a recent article from Mitch Leslie in Science illustrates. As a reality check and benchmark, the NUSI study will address whether the low-tech intervention of altering diet can be effective.
Lab Land has delved into NAFLD and its increasing prevalence in previous posts. Plenty of correlational data shows that sugar intake is linked to NAFLD (a recent paper from the Framingham Heart Study), but Vos points out that there are no studies showing that reducing sugar is sufficient to drive improvement in the disease.
Diet is a challenge to examine in humans rigorously. In observational studies, investigators are always bumping up against the limits of memory and accurate reporting. In an interventional study with adults, itâ€™s possible to provide them a completely defined menu forÂ a short timeÂ in a closed environment, but thatâ€™s less practical for longer periods or with children.
The press release announcing the NUSI study says: half of the families will eat and drink what they normally do while the rest will be put on sugar-free meals and snacks, all of which will be provided for the participants and their families for eight weeks.
Miriam Vos, MD
I was curious about how this would work, especially for boys aged 11 to 16 (theÂ participants in her study), so I asked Vos more about it for Lab Land.
â€œWe try to provide them a diet that is otherwise similar to what the family is used to,â€ she says. â€œFor example, if theyâ€™re accustomed to home-cooked meals, our team of nutritionists will work with them to find different recipes.â€ Read more
Tetherin is a host cell factor that mechanically links HIV-1 to the plasma membrane. This is the first time anyone has imaged tethered HIV-1 by cryo-electron tomography. In doing so, we were able to learn about the length and arrangement of the tethers.
Cryo-electron tomography is an imaging technique which enables scientists to look at biological specimens in a â€œnative-likeâ€ (frozen hydrated) state, without the chemical fixatives or heavy metal stains typically used for conventional electron microscopy.
The 3D reconstruction was manually segmented to highlight the different viral and cellular components: HIV-1 virions (lavender), mature conical-cores (aqua blue), immature Gag lattice (pink), plasma membrane (peach), rod-like tethers (sea green).
Pediatric infectious disease specialist Tracey Lamb earned recognition this week for her NIH New Innovator award. The goal of Lambâ€™s project is to develop a probiotic yeast as a platform for inexpensive oral vaccines.
â€œWe have a long way to go to develop this vaccine Magliette Calcio A Poco Prezzo delivery system to the point where it is ready for testing in the clinic,â€ she says. â€œNow my lab can undertake more intensive research on this project to demonstrate that our design is effective in protecting against infection.”
1. The probiotic yeast Lamb is planning to develop as a vaccine platform is Saccharomyces boulardii, which has been tested in clinical trials as a treatment for gastrointestinal disorders such as Clostridium dificile infection and several forms of diarrhea. It was originally isolated in the 1920s from fruit in Southeast Asia.
2. Saccharomyces boulardii is very close to standard bakerâ€™s yeast, Saccharomyces cerevisiae, and is actually considered a subspecies of S. cerevisiae. Genomic differences that http://www.magliettedacalcioit.com contribute to its probiotic properties are under investigation.
3. The New Innovator program, running since 2007, is one of the ways the National Institutes of Health seeks to reward especially creative or potentially transformative research proposals. The New Innovator awards, up to $1.5 million over five years, are meant for newly independent researchers building their careers. Lamb managed to snag Emoryâ€™s first.
In Americaâ€™s battle against obesity, there is some good news. According to a study conducted by Emory researchers, Americans consumed nearly a quarter less added sugars in 2008 than they did 10 years earlier.
The study, published in the American Journal of Clinical Nutrition in July 2011, found that the consumption of added sugars, such as those found in sodas, sports drinks, juices and sweetened dairy products, decreased among all age groups over a decade. The largest decrease came in the consumption of sodas, traditionally the largest contributor to added sugar consumption, according to Jean Welsh, MPH, PhD, RN, study author and post-doctoral fellow in pediatric nutrition at Emory University School of Medicine.
â€œWhile we were hopeful this would be the case, we were surprised when our research showed such a substantial reduction in the amount of added sugar Americans are consuming,â€ said Welsh. â€œWeâ€™re hopeful this trend will continue.â€
So, why the change? One of Welshâ€™s partners in the study, Miriam Vos, MD, MSPH, an assistant professor of pediatrics in the Emory University School of Medicine, and a physician on staff at Childrenâ€™s Healthcare of Atlanta, attributes much of the shift to public education.
â€œOver the past decade, there has been a lot of public health awareness about obesity and nutrition, and I think people are starting to get the message about sugar,â€ says Vos. â€œWeâ€™re not trying to send a message that sugar is inherently bad. Itâ€™s more that the large amounts of sugar we consume are having negative effects on our health, including increasing our risk of obesity, diabetes and cardiovascular disease.â€
The study interpreted data of 40,000 peopleâ€™s diets collected by the Centers for Disease Control and Prevention (CDC) over 10 years.Â From the surveys, researchers were able to calculate how much added sugar â€“ that is sugar that is not originally part of a food â€“ that Americans are consuming. In 1999-2000, the typical personâ€™s daily diet included approximately 100 grams of added sugar, a number that had dropped to 77 grams by 2007 and 2008.
While the study shows that the amount of added sugar Americans are consuming is lower, it doesnâ€™t mean the amount is low enough.
â€œThe American Heart Association recommends that we get about five percent of our calories from added sugars,â€ says Vos. â€œIn 1999 to 2000, people were consuming about 18 percent of their calories from added sugars. Over 10 years, that amount decreased to 14.5 percent of our daily calories, which is much better. But, clearly, 14.5 percent is still three times more than what is considered a healthy amount. Weâ€™re on the right track, but we still have room for improvement.â€