Update on SIV remission studies

Recently presented insights on how an antibody used to treat intestinal diseases can suppress Read more

Granulins treasure not trash - potential FTD treatment strategy

Granulins are of interest to neuroscientists because mutations in the granulin gene cause frontotemporal dementia (FTD). However, the functions of granulins were previously Read more

Blood vessels and cardiac muscle cells off the shelf

How to steer induced pluripotent stem cells into becoming endothelial cells, which line blood Read more

Retaining the resistance: MCR-1, colistin + lysozyme

If you’ve been following the news about antibiotic resistant bacteria, you may have heard about a particularly alarming plasmid: MCR-1. A plasmid is a circle of DNA that is relatively small and mobile – an easy way for genetic information to spread between bacteria. MCR-1 raises concern because it provides bacteria resistance against the last-resort antibiotic colistin. The CDC reports MCR-1 was found in both patients and livestock in the United States this summer.
David Weiss, director of Emory’s Antibiotic Resistance Center, and colleagues have a short letter in The Lancet Infectious Diseases showing that MCR-1 also confers resistance to an antimicrobial enzyme produced by our bodies called lysozyme. MCR-1-containing strains were 5 to 20 times less susceptible to lysozyme, they report.
This suggests that the pressure of fighting the host immune system may select for MCR-1 to stick around, even in the absence of colistin use, the authors say.
While the findings are straightforward in bacterial culture, Weiss cautions that there is not yet evidence showing that this mechanism occurs in live hosts. For those that really want to get alarmed, he also calls attention to a recent Nature Microbiology paper describing a hybrid plasmid with both MCR-1 and resistance to carbapenem, another antibiotic.

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Let’s not elope

Elopement may sound cute, because the word evokes a starry-eyed couple running away to get married. Elopement also refers to when a child runs or wanders from a safe, supervised environment. It can be a worrisome concern among the parents and caregivers of children with autism spectrum disorder and/or intellectual disability.

Here is a straightforward post from Seattle Children’s on elopement. Cathy Rice, now director of Emory Autism Center and previously at the CDC, has published two papers on elopement.

This May, Nathan Call, director of Severe Behavior Programs at Marcus Autism Center, and colleagues published a retrospective review of their behavioral treatments for elopement, extending back to 2003. This is a companion to their 2015 analysis of treatment for pica, the ingestion of inedible substances. Call is also assistant professor of pediatrics at Emory University School of Medicine.

He summarized their approach by saying: “Individualizing treatment based upon the reason each child elopes seems to work very well.” The paper makes it clear that the reasons for a child eloping were a mixed bag: for some it was “access to preferred tangible items,” for others it was access to attention or other reasons.

Elopement can be difficult to study scientifically because the consequences of just letting it happen may be disastrous. In an interview, Call described one child who was attracted by balloons. He eloped so readily that he had been struck by cars twice, one time because he was drawn to a balloon display at a nearby apartment complex.

The 11 children in the review were ages 5 to 12, and 7 had a diagnosis of autism spectrum disorder – others had Down syndrome or intellectual disability. Read more

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Background links on SIV remission Science paper

This was the first consistent demonstration of post-treatment immune control in monkeys infected with SIV, without previous vaccination. Long-term post-treatment control of HIV has been reported in only a handful of people treated soon after infection. To learn more, check out these links.

Transient SIVmac remission induced by TLR7 agonist, reported at 2016 CROI conference

Immune control of SIVagm, no antiretroviral drugs necessary. Model of “elite controllers.”

Immune clearance of SIVmac; prior CMV-based vaccination necessary.

Post-treatment control of HIV – VISCONTI study. Roundup of HIV remission cases, from Treatment Action Group. Read more

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A glimpse into the genetics of positive emotions

 

Happiness can be elusive, both in personal life and as a scientific concept. That’s why this paper, recently published in Molecular Psychiatry, seemed so striking.

A genome-wide association study of positive emotion identifies a genetic variant and a role for microRNAs.” Translation: a glimpse into the genetics of positive emotions.

Editorial note: Although the research team here is careful and confirms the findings in independent groups and in brain imaging and fear discrimination experiments, this is a preliminary result. More needs to be explored about how these genetic variants and others affect positive emotions.

“With relatively few studies on genetic underpinnings of positive emotions, we face the challenges of a nascent research area,” the authors write.

Perhaps ironically, the finding comes out of the Grady Trauma Project, a study of inner-city residents exposed to high rates of abuse and violence, aimed at understanding mechanisms of resilience and vulnerability in depression and PTSD.

“Resilience is a multidimensional phenomenon, and we were looking at just one aspect of it,” says first author Aliza Wingo. She worked with Kerry Ressler , now at Harvard, and Tanja Jovanovic and other members of the Grady Trauma Project team.

“Positive affect” is what the team was measuring, through responses on questionnaires. And the questions are asking for the extent that respondents feel a particular positive emotion in general, rather than that day or that week. Read more

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Gestational age estimated via DNA methylation

Researchers have developed a method for estimating developmental maturity of newborns. It is based on tracking DNA methylation, a structural modification of DNA, whose patterns change as development progresses before birth.

The new method could help doctors assess developmental maturity in preterm newborns and make decisions about their care, or estimate the time since conception for a woman who does not receive prenatal care during pregnancy. As a research tool, the method could help scientists study connections between the prenatal environment and health in early childhood and adulthood.

How advanced is the development of a newborn, possibly preterm baby? Geneticists have developed a method for estimating gestational age by looking at DNA methylation.

The study, led by Alicia Smith, PhD and Karen Conneely, PhD, used blood samples from more than 1,200 newborns in 15 cohorts from around the world. The results are published in Genome Biology.

Smith is an associate professor and vice chair of research for the Department of Gynecology and Obstetrics in the School of Medicine, and Conneely is an assistant professor in the Department of Human Genetics. The first author, Anna Knight, is a graduate student in the Genetics and Molecular Biology Program.

Gestational age, is normally estimated by obstetricians using ultrasound during the first trimester, by asking a pregnant woman about her last menstrual period, or by examining the baby at birth. Ultrasound is considered to be the most precise estimate of gestational age. This work extends upon earlier studies of DNA methylation patterns that change over development and predict age and age-related health conditions in children and adults.

The Emory team gathered DNA methylation data from previous studies examining live births and health outcomes, and used an unbiased statistical learning approach to select 148 DNA methylation sites out of many thousands in the genome. By examining methylation at those sites, gestational age could be accurately estimated between 24 and 44 weeks, the authors report. The median difference between age determined by DNA methylation and age determined by an obstetrician estimate was approximately 1 week.

The researchers also found that the difference between a newborn’s age predicted by DNA methylation and by an obstetrician may be another indicator of developmental maturity, and is correlated with birthweight, commonly used as an indicator of perinatal health. Read more

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Strength tests for platelets

Bleeding disorders could one day be diagnosed by putting platelets through strength tests, researchers have proposed.

Biomedical engineers from Emory and Georgia Tech have devised a microfluidic testing ground where platelets can demonstrate their strength by squeezing two protein dots together. Imagine rows and rows of strength testing machines from a carnival, but very tiny. Platelets are capable of exerting forces that are several times larger, in relation to their size, in comparison with muscle cells.

After a blood clot forms, it contracts, promoting wound closure and restoration of normal blood flow. This process can be deficient in a variety of blood clotting disorders. Previously, it was difficult to measure individual platelet’s contributions to contraction, because clots’ various components got in the way.

The prototype diagnostic tools are described in Nature Materials.

platelet_strength_test

Top: platelets exert their strength. Bottom left: red = platelets, green = fibrinogen dots. Bottom right: size of actual device.

“We discovered that platelets from some patients with bleeding disorders are ‘wimpier’ than platelets from healthy people,” says Wilbur Lam, MD, PhD, assistant professor in the Department of Pediatrics at Emory University School of Medicine and in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “Our device may function as a new physics-based method to test for bleeding disorders, complementary to current methods.”

The first author of the paper is instructor David Myers, PhD. Lam is also a physician in the Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta. Collaborators at North Carolina State University led by Ashley Brown, PhD, contributed to testing the device.

The scientists infer how strong or wimpy someone’s platelets are by measuring how far the protein dots move, taking a picture of the rows of dots, and then analyzing the picture on a computer. The dots are made of fibrinogen, a sticky protein that is the precursor for fibrin, which forms a mesh of insoluble strands in a blood clot.

In addition to detecting problems with platelet contraction in patients with known inherited disorders such as Wiskott Aldrich syndrome, Myers, Lam and colleagues could also see differences in some patients who had bleeding symptoms, but who performed normally on standard diagnostic tests. Read more

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Tapping evolution to improve biotech products

Scientists can improve protein-based drugs by reaching into the evolutionary past, a paper published this week in Nature Biotechnology proposes.

As a proof of concept for this approach, the research team from Emory, Children’s Healthcare of Atlanta and Georgia Tech showed how “ancestral sequence reconstruction” or ASR can guide engineering of the blood clotting protein known as factor VIII, which is deficient in the inherited disorder hemophilia A.

fviii_2r7e

Structure of Factor VIII

Other common protein-based drugs include monoclonal antibodies, insulin, human growth hormone and white blood cell stimulating factors given to cancer patients. The authors say that ASR-based engineering could be applied to other recombinant proteins produced outside the human body, as well as gene therapy.

It has been possible to produce human factor VIII in recombinant form since the early 1990s. However, current factor VIII products still have problems: they don’t last long in the blood, they frequently stimulate immune responses in the recipient, and they are difficult and costly to manufacture.

Experimental hematologist and gene therapist Chris Doering, PhD and his colleagues already had some success in addressing these challenges by filling in some of the sequence of human factor VIII with the same protein from pigs.

“We hypothesized that human factor VIII has evolved to be short lived in the blood to reduce the risk of thrombosis,” Doering says. “And we reasoned that by going even farther back in evolutionary history, it should be possible to find more stable, potent relatives.”

Doering is associate professor of pediatrics at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center of Children’s Healthcare of Atlanta. The first author of the paper is former Molecular and Systems Pharmacology graduate student Philip Zakas, PhD.

Doering’s lab teamed up with Trent Spencer, PhD, director of cell and gene therapy for the Aflac Cancer and Blood Disorders Center, and Eric Gaucher, PhD, associate professor of biological sciences at Georgia Tech, who specializes in ASR. (Gaucher has also worked with Emory biochemist Eric Ortlund – related item on ASR from Gaucher)

ASR involves reaping the recent harvest of genome sequences from animals as varied as mice, cows, goats, whales, dogs, cats, horses, bats and elephants. Using this information, scientists reconstruct a plausible ancestral sequence for a protein in early mammals. They then tweak the human protein, one amino acid building block at a time, toward the ancestral sequence to see what kinds of effects the changes could have. Read more

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Vaccine vs many common cold viruses achievable

Scientists are making the case that a vaccine against rhinoviruses, the predominant cause of the common cold, is achievable.

The quest for a vaccine against rhinoviruses may have seemed quixotic, because there are more than 100 varieties circulating around the world. Even so, the immune system can handle the challenge, researchers from Emory University School of Medicine and Children’s Healthcare of Atlanta say.

Martin Moore, PhD

Martin Moore, PhD

Vaccines that combine dozens of varieties of rhinovirus at once are effective in stimulating antiviral antibodies in mice and monkeys, the researchers report in Nature Communications. The paper was also posted on Biorxiv before publication.

“We think that creating a vaccine for the common cold can be reduced to technical challenges related to manufacturing,” says Martin Moore, PhD, associate professor of pediatrics at Emory University School of Medicine and Children’s Healthcare of Atlanta. Read more

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Anticancer strategy: expanding what is druggable

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.”

fx1-1Many 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 Cell disable 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.

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Bile acid uptake inhibitor prevents NASH/fatty liver in mice

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.”

Karpen is Raymond F. Schinazi distinguished professor of pediatrics at Emory University School of Medicine and chief of the Division of Pediatric Gastroenterology, Hepatology and Nutrition at Children’s Healthcare of Atlanta. He and Paul Dawson, PhD, Emory professor of pediatrics, jointly run a lab that investigates the role of bile acids in liver disease.

Saul Karpen, MD, PhD

Saul Karpen, MD, PhD

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

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