Beyond the amyloid hypothesis: proteins that indicate cognitive stability

If you’re wondering where Alzheimer’s research might be headed after the latest large-scale failure of a clinical trial based on the “amyloid hypothesis,” check this Read more

Mother's milk is OK, even for the in-between babies

“Stop feeding him milk right away – just to be safe” was not what a new mother wanted to hear. The call came several days after Tamara Caspary gave birth to fraternal twins, a boy and a girl. She and husband David Katz were in the period of wonder and panic, both recovering and figuring out how to care for them. “A nurse called to ask how my son was doing,” says Caspary, a developmental Read more

Focus on mitochondria in schizophrenia research

Despite advances in genomics in recent years, schizophrenia remains one of the most complex challenges of both genetics and neuroscience. The chromosomal abnormality 22q11 deletion syndrome, also known as DiGeorge syndrome, offers a way in, since it is one of the strongest genetic risk factors for schizophrenia. Out of dozens of genes within the 22q11 deletion, several encode proteins found in mitochondria. A team of Emory scientists, led by cell biologist Victor Faundez, recently analyzed Read more

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Talking to members of Congress: how-to for scientists

It’s OK to use the term “pH” when talking with a member of Congress – but not the word “intracellular.”

This was one of the rules of thumb that emerged from Adam Katz’ talk at the GDBBS Student Research Symposium Friday afternoon. Katz, a public policy specialist at Research America, was advising Emory graduate students and faculty on the best ways to advocate for biomedical research. His theme: get personal.

That is, he advised scientists to meet in person with members of Congress or people on their staffs, try to get them to remember you, and invite them to come visit your laboratory. Make a personal connection. Read more

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Odd couples and persistence

When doctors treat disease-causing bacteria with antibiotics, a few bacteria can survive even if they do not have a resistance gene that defends them from the antibiotic. These rare, slow-growing or hibernating cells are called “persisters.”

Microbiologists see understanding persistence as a key to fighting antibiotic resistance and possibly finding new antibiotics. Persistence appears to be regulated by constantly antagonistic pairs of proteins called toxin-antitoxins.

Basically, the toxin’s job is to slow down bacterial growth by interfering with protein production, and the antitoxin’s job is to restrain the toxin until stress triggers a retreat by the antitoxin. Some toxins chew up protein-encoding RNA messages docked at ribosomes, but there are a variety of mechanisms. The genomes of disease-causing bacteria are chock full of these battling odd couples, yet not much was known about how they work in the context of persistence.

Biochemist Christine Dunham reports that several laboratories recently published papers directly implicating toxin-antitoxin complexes in both persistence and biofilm formation. Her laboratory has been delving into how the parts of various toxin-antitoxin complexes interact.HigBA smaller

BCDB graduate student Marc Schureck and colleagues have determined the structure of a complex of HigBA toxin-antitoxin proteins from Proteus vulgaris bacteria via X-ray crystallography. The results were recently published in Journal of Biological Chemistry.

While Proteus vulgaris is known for causing urinary tract and wound infections, the HigBA toxin-antitoxin pair is also found in several other disease-causing bacteria such as V. cholera, P. aeruginosa, M. tuberculosis, S. pneumoniae etc.

“We have been directly comparing toxin-antitoxin systems in E. coli, Proteus and M. tuberculosis to see if there are commonalities and differences,” Dunham says.

The P. vulgaris HigBA structure is distinctive because the antitoxin HigA does not wrap around and mask the active site of HigB, which has been seen in other toxin-antitoxin systems. Still, HigA clings onto HigB in a way that prevents it from jamming itself into the ribosome.

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Cellular response to stress: autophagy

Update: Yoshinori Ohsumi’s 2016 Nobel Prize was for the study of autophagy. Hepatologist Mark Czaja, who came to Emory in 2015, is well known for his work on autophagy in the liver.

Feeling hungry? For this month’s Current Concept feature, lets take a look at the term autophagy. Taken literally, its Greek roots mean “self-digestion”.

Autophagy in mouse liver cells — the autophagic vesicles are green (Image from PNAS)

Autophagy is a basic response of cells to not having enough nutrients or other forms of stress: they begin to break down parts of the cell that are broken or not needed. The term autophagy was coined by Belgian biochemist Christian de Duve in the 1960s. He discovered lysosomes, the parts of the cell where breakdown can take place.

Autophagy comes up in many contexts in biomedical research. Indeed, there is an entire scientific journal devoted to the topic. At Emory, researchers interested in cancer, Parkinson’s, stroke and liver disease all have touched upon the process of autophagy.  Read more

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How beneficial bacteria talk to intestinal cells

Guest post from Courtney St Clair Ardita, MMG graduate student and co-author of the paper described. Happy Halloween!

In the past, reactive oxygen species were viewed as harmful byproducts of breathing oxygen, something that aerobic organisms just have to cope with to survive. Not any more. Scientists have been finding situations in humans and animals where cells create reactive oxygen species (ROS) as signals that play important parts in keeping the body healthy.

One example is when commensal or good bacteria in the gut cause the cells that line the inside of the intestines to produce ROS. Here, ROS production helps repair wounds in the intestinal lining and keeps the environment in the gut healthy. This phenomenon is not unique to human intestines. It occurs in organisms as primitive as fruit flies and nematodes, so it could be an evolutionarily ancient response. Examples of deliberately created and beneficial ROS can also be found in plants, sea urchins and amoebas.

Researchers led by Emory pathologist Andrew Neish have taken these findings a step further and identified the cellular components responsible for producing ROS upon encountering bacteria. Postdoctoral fellow Rheinallt Jones is first author on the paper that was recently published in The EMBO Journal. Read more

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Visualizing retrograde flow

This month’s intriguing image is a set of videos produced by cell biologist James Zheng’s laboratory. Looking at this video of a cell can be mesmerizing. The edges of the cell appear to be flowing inward, like a waterfall. Zheng explains that this is a phenomenon called “actin retrograde flow.”

Actin is a very abundant protein found in animals, plants and fungi that forms filaments, making up the cell’s internal skeleton. What we are seeing with retrograde flow is that molecules of actin are being added to one end of the filaments while coming loose from the other end.Actin

Zheng’s laboratory is studying a protein called cofilin, which disassembles actin filaments. Using a technique called CALI (chromophore-assisted laser inactivation) the scientists http://www.troakley.com/ used a laser to blast cofilin, inactivating it. This is why, partway through the loop, after the word CALI appears, the flow slows down. Postdoctoral fellow Eric Vitriol is the lead author on a paper in Molecular Biology of the Cell that includes these videos.

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Gene duplication leads to obesity in childhood syndrome

A team of researchers has discovered a genetic syndrome that causes childhood obesity, intellectual disability and seizures. The syndrome comes from an “unbalanced” chromosomal translocation: affected individuals have additional copies of genes from one chromosome and fewer copies of genes from another.

The results were published this week in Proceedings of the National Academy of Sciences, Early Edition.

Katie Rudd, PhD, assistant professor of human http://www.raybanoutletes.com/ genetics at Emory University School of Medicine, is senior author of the paper. Research specialist Ian Goldlust, now a graduate student in the NIH-Oxford-Cambridge Scholars Program, is the first author. Co-authors include investigators from around the USA and Australia.

Rudd’s team was able to connect the contribution of one gene, GNB3, among many involved in the translocation, to the obesity aspect of the syndrome. Her lab created a mouse model with an extra copy of the GNB3 gene and found that the mice are obese. The mice are on average 6 percent (males) or 10 percent (females) heavier.

Rudd says her work was greatly assisted by collaboration with the Unique Rare Chromosome Disorder Support Group, a UK-based charity. Within Unique, a few parents had together found that their children had translocations involving the same chromosomes and similar symptoms. They contacted Rudd and helped her find additional affected families. Her study includes seven unrelated patients.

“It really was a group effort, and Unique was the linchpin,” she says. “Managing to find seven families with exactly the same rare translocation would have been extremely difficult otherwise.”

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Exception from informed consent: what patients say

Informed consent is a basic principle of clinical research. Doctors are required to make sure that patients understand what’s involved with experimental treatments, and patients should only participate if they provide consent.

However, an important area of clinical research takes place outside of this general rule, because some life-threatening conditions – seizures, traumatic brain injury and cardiac arrest, as examples — make it impossible for the patient to learn about a clinical trial and make a decision about whether to participate. The urgency of treatment can also mean that seeking proxy consent from a relative is impractical.

A recent editorial in USA Today highlights this area of research, called EFIC (exception from informed consent). The author, Katherine Chretien from George Washington University, cites research from Emory investigators Neal Dickert and Rebecca Pentz.

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The creeping edges of cells: lamellipodia

Lamellipodia with red box
This month’s Image feature highlights lamellipodia, the thin sheet-like regions at the leading edges of migrating cells. Lamellipodia act as tiny creeping motors that pull the cell forward.

To help visualize lamellipodia, Adriana Simionescu-Bankston, a graduate student in Grace Pavlath’s lab, provided us with this photo of muscle cells. The red box shows an example of lamellipodia. Notice the edge of the cell, where the green color is more intense.

The green color comes from FITC-phalloidin, which stains F-actin, the Ray Ban outlet filaments that make up a large part of the cells’ internal skeleton. (Phalloidin is an actin-binding toxin originally isolated from death cap mushrooms, and FITC is what makes it green.) The blue color comes from DAPI, a dye that stains the DNA in the nucleus.

Simionescu-Bankston and Pavlath recently published a paper in the journal Developmental Biology, examining the function of a protein called Bin3 in muscle development and regeneration. They found that Bin3 appears to regulate lamellipodia formation; in mice that lack Bin3, muscle cells have fewer lamellipodia and the muscle tissues regenerate slower after injury. Bin3 is also important in the eye, since the “knockout” mice develop cataracts soon after birth.

 

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From the genetic code to new antibiotics

Biochemist Christine Dunham and her colleagues have a new paper in PNAS illuminating a long-standing puzzle concerning ribosomes, the factories inside cells that produce proteins.

Ribosomes are where the genetic code “happens,” because they are the workshops where messenger RNA is read out and proteins are assembled piece by piece. As a postdoc, Dunham contributed to Nobel Prize-winning work determining the molecular structure of the ribosome with mentor Venki Ramakrishnan.

Ribosomes are the workshops for protein synthesis and the targets of several antibiotics

The puzzle is this: how messenger RNA can be faithfully and precisely translated, when the interactions that hold RNA base pairs (A-U and G-C) together are not strong enough. There is enough “wobble” in RNA base pairing such that transfer RNAs that don’t match all three letters on the messenger RNA can still fit.

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Supreme decision on DNA patents

In these days of political polarization, how often does the United States Supreme Court make a unanimous decision? When the case has to do with human genes and their patentability!

The case concerned patents held by Utah firm Myriad Genetics on the BRCA1 and 2 genes. Mutations in those genes confer an increased risk of breast and ovarian cancer. The patents in dispute claimed the genes themselves rather than just the technology for reading them.

Cecelia Bellcross, director of Emory’s genetics counseling program and an expert on breast cancer genetics counseling, reports that “in general, the clinical genetics community is jumping up and down, as are a lot of genetics lab directors and definitely patient advocacy groups.”

Myriad’s BRCA tests cost more than $3,000. Several competing firms announced that they would offer tests for the BRCA1 and 2 mutations at significantly lower prices.

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