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

Heart

Blood versus the crypts

Amielle Moreno

For Halloween, Lab Land welcomes a guest post from Neuroscience graduate student Amielle Moreno, former editor of the Central Sulcus newsletter.

While recent studies have found evidence for the healing properties of blood from younger individuals, the fascination with “young blood” has been a part of the human condition for centuries.

In ancient Greece, Hippocrates introduced the concept that our health and temperament was controlled by the four humors, proposing that blood was the one responsible for courage, playfulness as well as hope. From the 16th century story of Countess Elizabeth Báthory de Ecsed of Hungary, the idea of “blood baths” acquired decidedly more sinister connotations.

The “Blood Countess” holds the Guinness World Record as the most prolific female murderer. With 80 confirmed kills, Báthory might have lured up to 650 peasant girls to her castle with the promise of work as maidservants or courtly training. Instead of etiquette lessons, they were burned, beaten, frozen or starved for the Countess’ sadistic pleasure. Folk stories told how she would bathe in the blood of virgins to preserve her youth and beauty.

Portrait if Elizabeth Bathory, via Wikimedia

Portrait if Elizabeth Bathory, via Wikimedia

Humors remained a staple of traditional western medicine until the 1800s when medical research and our modern concept of medicine emerged. In this more enlightened age, people started sewing animals together to see what would happen.

In the mid-1800s, a French zoologist named Paul Bert first experimented with the creation of parabionts: the surgical joining of two animals, usually two rodents of the same species, in order to study the effect of one’s blood on the other. Read more

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How metabolic syndrome interacts with stress – mouse model

Emory researchers recently published a paper in Brain, Behavior and Immunity on the interaction between psychological stress and diet-induced metabolic syndrome in a mouse model.

“The metabolic vulnerability and inflammation associated with conditions present in metabolic syndrome may share common risk factors with mood disorders. In particular, an increased inflammatory state is recognized to be one of the main mechanisms promoting depression,” writes lead author Betty Rodrigues, a postdoc in Malu Tansey’s lab in the Department of Physiology.

This model may be useful for identification of possible biomarkers and therapeutic targets to treat metabolic syndrome and mood disorders. As a follow-up, Tansey reports that her team is investigating the protective effects of an anti-inflammatory agent on both the brain and the liver using the same model.

Metabolic syndrome and stress have a complex interplay throughout the body, the researchers found. For example, psychological stress by itself does not affect insulin or cholesterol levels, but it does augment them when combined with a high-fat, high-fructose diet. In contrast, stress promotes adaptive anti-inflammatory markers in the hippocampus (part of the brain), but those changes are wiped out by a high-fat, high-fructose diet.

The findings show synergistic effects by diet and stress on gut permeability promoted by inflammation, and the biliverdin pathway. Biliverdin, a product of heme breakdown, is responsible for a greenish color sometimes seen in bruises.

“Stress and high-fat high-fructose diet promoted disturbances in biliverdin, a metabolite associated with insulin resistance,” Rodrigues writes. “To the best of our knowledge, our results reveal for the first time evidence for the synergistic effect of diet and chronic psychological stress affecting the biliverdin pathway.”

Read more

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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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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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Sensory connections spill over in synesthesia

Neuroscientists at Emory University have found that people who experience a mixing of the senses, known as synesthesia, are more sensitive to associations everyone has between the sounds of words and visual shapes. The results are published in the European Journal of Neuroscience.

Synesthesia is a stable trait, and estimated to be present in 1 to 4 percent of people. It can be inherited, although the precise genes have not been identified. One of the most common forms of synesthesia is when people involuntarily see particular colors in connection with letters, numbers or sounds.

Many artists and composers have described their experiences with synesthesia. Children with synesthesia say sometimes that it is distracting when they are trying to read. Thus, understanding the origins of synesthesia may help people with dyslexia or other learning differences, or people who have lost their sight or hearing and are trying to engage in sensory substitution for rehabilitation.

Researchers led by neurologist Krish Sathian, MD, PhD, recruited 17 people with synesthesia, and asked them to take a form of the IAT (implicit association test). Known for its use probing social attitudes such as racial prejudice, the IAT can also assess “cross-modal correspondences.”

An example of a cross-modal correspondence is that we describe musical notes as being “high” or “low” – words that also signify relative positions in space. Another is that we think of some sounds such as “m” and “l” as soft, and are more likely to associate them with rounded shapes. Similarly, we connect hard sounds such as “k” and “t” with angular shapes.

“There’s been a debate about synesthesia,” Sathian says. “Are the associations synesthetes have just extreme versions of cross-modal correspondences that other people have, or are they qualitatively different?”

Sathian and his colleagues found that people with synesthesia were more sensitive to correspondences between the sounds of pseudowords — words without meaning in English — and rounded or angular shapes. Read more

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Strain differences in Zika infection genes

Scientists have revealed molecular differences between how the African and Asian strains of Zika virus infect neural progenitor cells. The results could provide insights into the Zika virus’ recent emergence as a global health emergency, and also point to inhibitors of the p53 pathway as potential leads for drugs that could protect brain cells from cell death.

The findings, from the Emory/Johns Hopkins/Florida State team that showed this spring that neural progenitor cells are particularly vulnerable to Zika infection (related paper), were published this week in Nucleic Acid Research. The manuscript was also posted on BioRxiv before publication.

Zika infection genes

Overlap in gene expression changes when neural progenitor cells are infected by African or Asian strains of Zika virus. Diagram from Nucleic Acids Research via Creative Commons.

Zika virus was first discovered in Uganda in the 1940s, and two distinct lineages of Zika diverged sometime in the second half of the 20th century: African and Asian. The strains currently circulating in the Western Hemisphere, which have been linked to microcephaly in infants and Guillain-Barre syndrome in adults, are more closely related to the Asian lineage.

The research team catalogued and compared genes turned on and off by Asian and African strains of Zika virus, as well as dengue virus, in human neural progenitor cells. The authors describe dengue as inducing more robust changes in gene expression than either strain of Zika. Although they show that dengue can infect neural progenitor cells like Zika can, dengue infection does not stunt the cells’ growth or lead to cell death.

“This shows that the differences between Zika and dengue are not at the level of being able to infect neural progenitors, but more about the harm Zika causes when it does infect those cells,” says senior author Peng Jin, PhD, professor of human genetics at Emory University School of Medicine. Read more

Posted on by Quinn Eastman in Neuro 1 Comment

Cell therapy clinical trial in stroke

Emory neurosurgeon Robert Gross was recently quoted in a Tennessee newspaper article about a clinical trial of cell therapy for stroke. He used cautionary language to set expectations.

“We’re still in the very early exploratory phases of this type of work,” Gross told the Chattanooga Times Free Press. “In these cases, a significant area of the brain has been damaged, and simply putting a deposit of undifferentiated cells into the brain and magically thinking they will rewire the brain as good as new is naive. None of us think that.”

A more preliminary study (just 18 patients) using the same approach at Stanford and University of Pittsburgh was published this summer in Stroke, which says it was the “first reported intracerebral stem cell transplant study for stroke in North America.” The San Diego Union Tribune made an effort to be balanced in how the results were described:

Stroke patients who received genetically modified stem cells significantly recovered their mobility… Outcomes varied, but more than a third experienced significant benefit.

The newspaper articles made us curious about what these cells actually are. They’re mesenchymal stromal cells, engineered with an extra modified Notch gene. That extra gene drives them to make more supportive factors for neurons, but it doesn’t turn them into neurons. Read more

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HD monkeys display full spectrum of symptoms seen in humans

Transgenic Huntington’s disease monkeys display a full spectrum of symptoms resembling the human disease, ranging from motor problems and neurodegeneration to emotional dysregulation and immune system changes, scientists at Yerkes National Primate Research Center, Emory University report.

The results, published online in the journal Brain, Behavior and Immunity, strengthen the case that transgenic Huntington’s disease monkeys could be used to evaluate emerging treatments (such as this) before launching human clinical trials.

“Identifying emotional and immune symptoms in the HD monkeys, along with previous studies demonstrating their cognitive deficits and fine motor problems, suggest the HD monkey model embodies the full array of symptoms similar to human patients with the disease,” says Yerkes research associate Jessica Raper, PhD, lead author of the paper. Read more

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A sweet brain preserver: trehalose

It’s sweet, it’s safe, and it looks like it could save neurons. What is it? Trehalose.

Trehalose molecule

Trehalose is a natural sugar.

This natural sugar is used in the food industry as a preservative and flavor enhancer (it’s in Taco Bell’s meat filling). And curiously, medical researchers keep running into trehalose when they’re looking for ways to fight neurodegenerative diseases.

A recent example from Emory’s Department of Pharmacology: Chris Holler, Thomas Kukar and colleagues were looking for drugs that might boost human cells’ production of progranulin (PGRN), a growth factor that keeps neurons healthy. Mutations in the progranulin gene are a common cause of frontotemporal dementia.

The Emory scientists discovered two leads: a class of compounds called mTOR inhibitors — the transplant drug rapamycin is one — and trehalose. The team decided to concentrate on trehalose because it increased PGRN levels in neuronal and non-neuronal cell types, unlike the mTOR inhibitors. Their results were published at the end of June in Molecular Neurodegeneration.

The team confirmed their findings by examining the effects of trehalose on cells derived from patients with progranulin mutations. This paper is the first to include results from Emory’s Laboratory of Translational Cell Biology, which was established in 2012 to facilitate this type of “disease in a dish” approach. Cell biologists Charles Easley, Wilfried Rossoll and Gary Bassell from the LTCB, and neurologists Chad Hales and William Hu from the Center for Neurodegenerative Disease are co-authors.

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Four take-home thoughts on NGLY1

Please check out our feature in Emory Medicine magazine about two sisters with NGLY1 deficiency. This rare genetic disorder was identified only a few years ago, and now a surge of research is directed toward uncovering its mysteries.

  1. The Stinchcombs are amazing. Seth Mnookin’s July 2014 piece in the New Yorker, and especially, his comments at the end of an interview with The Open Notebook drove me to contact them. “The father cares for the two girls with this disease full time. The mother is working insane hours. And while all this is going on, they’re the most good-natured … I don’t know, they just seem like they’re happy.”
  1. Several research teams around the world are investigating NGLY1 deficiency and potential remedies. For the magazine article, I talked with Emory geneticist Michael Gambello, Hudson Freeze at Sanford Burnham and Lynne Wolfe at the NIH Undiagnosed Diseases Program. Even more: the Grace Science Foundation, established by the Wilsey family, is supporting research at Retrophin/Notre Dame and Gladstone/UCSF. The independent Perlstein lab is investigating NGLY1 deficiency in fruit flies (reminiscent of Emory research from a decade ago on Fragile X syndrome).
  1. There’s a long road ahead for rare genetic disorders such as NGLY1 deficiency. That’s why the title that EM editor Mary Loftus came up with, “In time to help Jessie,” is so poignant. When I read Abby Goodnough’s New York Times piece on RCDP, which is a rare inherited bone disease that also involves seizures, I thought: “That could be NGLY1 in ten years.” Still, progress is possible, as demonstrated by this recent NEJM report on exome sequencing and neurometabolic disorders from British Columbia.

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