Circadian rhythms go both ways: in and from retina

Removal of Bmal1 accelerates the deterioration of vision that comes with Read more

Genomics plus human intelligence

The power of gene sequencing to solve puzzles when combined with human Read more

'Master key' microRNA has links to both ASD and schizophrenia

Recent studies of complex brain disorders such as schizophrenia and autism spectrum disorder (ASD) have identified a few "master keys," risk genes that sit at the center of a network of genes important for brain function. Researchers at Emory and the Chinese Academy of Sciences have created mice partially lacking one of those master keys, called MIR-137, and have used them to identify an angle on potential treatments for ASD. The results were published this Read more

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Genomics plus human intelligence

Emory geneticists Hong Li and Michael Gambello recently identified the first pediatric case of a rare inherited metabolic disorder: glucagon receptor deficiency. Their findings, published in Molecular Genetics and Metabolic Reports, show the power of gene sequencing to solve puzzles – when combined with human intelligence. Although the diagnosis did not resolve all the issues faced by the patient, it allowed doctors to advise the family about diet and possible pancreatic tumor risk.

The family of a now 9-year-old girl came to Li when the girl was 4 years old. Based on newborn screening, the girl had been diagnosed with a known disorder called arginase deficiency. Arginase breaks down the amino acid arginine; if it is deficient, arginine and toxic ammonia tend to accumulate. At birth, the girl had high arginine levels – hence the initial diagnosis.

The girl had a history of low body weight, anorexia and intermittent vomiting, which led doctors to place a feeding tube through the abdominal wall into her stomach. For several years, she was given a special low-protein liquid diet and supplements, aimed at heading off nutritional imbalance and tissue breakdown. However, she did not have intellectual disability or neurological symptoms, which are often seen with arginase deficiency.

In fact, her blood amino acids, including arginine, were fully normalized, and a genetic test for arginase deficiency was normal as well.  These results were perplexing. By reviewing all the clinical, biochemical and molecular data, Li concluded the girl did not have arginase deficiency, and began looking for an alternative diagnosis. Read more

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Shape-shifting RNA regulates viral sensor

Congratulations to Emory biochemists Brenda Calderon and Graeme Conn. Their recent Journal of Biological Chemistry paper on a shape-shfting RNA was selected as an Editor’s Pick and cited as a “joy to read… Technically, the work is first class, and the writing is clear.”

Calderon, a former BCDB graduate student and now postdoc, was profiled by JBC in August.

Brenda Calderon, PhD

Calderon and Conn’s JBC paper examines regulation of the enzyme OAS (oligoadenylate synthetase). OAS senses double-stranded RNA: the form that viral genetic material often takes. When activated, OAS makes a messenger molecule that drives internal innate immunity enzymes to degrade the viral material (see below).

OAS is in turn regulated by a non-coding RNA, called nc886. Non-coding means this RNA molecule is not carrying instructions for building a protein. Calderon and Conn show that nc886 takes two different shapes and only one of them activates OAS.

Conn says in a press release prepared by JBC that although nc886 is present in all human cells, it’s unknown how abundance of its two forms might change in response to infection. Read more

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Tracking a frameshift through the ribosome

Ribosomes, the factories that assemble proteins in cells, read three letters of messenger RNA at a time. Occasionally, the ribosome can bend its rules, and read either two or four nucleotides, altering how downstream information is read: frameshifting.

This week, Christine Dunham’s lab in the Department of Biochemistry has a paper in PNAS on how ribosomal frameshifting works, one of several she has published on this topic. The first author is postdoc Samuel Hong, now at MD Anderson. A commentary in PNAS calls their paper a “major advance” and “culmination of a half-century quest.”

A suppressor tRNA can occupy more than one site on the ribosome. Adapted figure courtesy of Christine Dunham

Some antibiotics disrupt protein synthesis by encouraging frameshifting to occur, so a thorough understanding of frameshifting benefits antibiotic research. Also, scientists are aiming to use the process to customize proteins for industrial and pharmaceutical applications, by inserting amino acid building blocks not found in nature.

When mutations add or subtract a letter from a protein-coding gene, that usually turns the rest of the gene to nonsense. Compensatory mutations in the same gene can push the genetic letters back into the correct frame. However, others are separate, found within the machinery for translating the genetic code, namely transfer RNAs: the adaptors that bring amino acids into the ribosome. Suppressor tRNAs can compensate for a forward frameshift in another gene.

The Dunham lab’s new paper solves the structure of a bacterial ribosome undergoing “recoding” influenced by a suppressor tRNA. Her group had previously captured how the ribosomes decode this tRNA in one site of the ribosome, the aminoacyl or A site, in a 2014 PNAS paper. The new structures show how the tRNA moves through the ribosome out-of-frame to recode. The tRNA undergoes unusual rearrangements that cause the ribosome to lose its grip on the mRNA frame and allows the tRNA to form new interactions with the ribosome to shift into a new reading frame.

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Learn about science writing careers from a pro

In November, Emory’s Office of Postdoctoral Education will be having a workshop on science writing in November, with special guest Marina Damiano. She is a scientist with corporate experience at an advertising/marketing communications/PR agency for life science and healthcare companies. While her workshop is now overscheduled (suggesting an abundance of interest!), Damiano is giving a career talk as well.

• Career Seminar. Wed, Nov 14th, 12 – 1.30 pm, SOM 178-P Hear Damiano discuss her background and career path, giving advice for anyone interested in pursuing a career in science communications. Open to everyone: undergraduates, grad students and postdocs.

Thanks for the tip from Claire Jarvis, editor of the Emory Postdoctoral Association Magazine. We are looking forward to the next issue, which we hear is focused on microbiome topics.

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Focus on antibiotic resistance at ASM Microbe 2018

We are excited that the ASM Microbe meeting will be at the Georgia World Congress Center from June 7 to June 11. If you are interested in antibiotic resistance, you can learn about how to detect it, how to (possibly) defeat it and how the bacteria fight back.

A host of Emory microbiologists are participating. In some cases, our scientists are presenting their unpublished data for discussion with their colleagues at other universities. Accordingly, we are not going to spill the beans on those results. However, please find below some examples of who’s talking and a bit of explanatory background. ASM Microbe abstracts are available online for posters, but not for some symposiums and plenary talks.

David Weiss labKlebsiella

Graduate student Jessie Wozniak is presenting her research on an isolate of Klebsiella that combines alarming properties. She will describe how the bacterial colonies behave (unappetizingly) like stretchy melted cheese in a “string test.”

June 9, 11 am to 1 pm, June 11, 11 am to 1 pm

Christine Dunham – toxin-antitoxin/persistence

Graduate student Sarah Anderson presenting her poster at ASM Microbe. She discussed a genetic connection between virulence switch and antibiotic resistance.

Dunham, a structural biologist, is giving a plenary talk June 11 on toxin-antitoxin pairs, which play a role in regulating bacterial persistence, a dormant state that facilitates antibiotic resistance. Two past papers from her lab.

Phil Rather labAcinetobacter baumannii

Rather’s lab recently published a Nature Microbiology paper on A. baumannii’s virulence/opacity switch. This type of bacteria is known for hospital-associated infections and for wound infections in military personnel. Poster talk by graduate student Sarah Anderson June 8. Read more

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What are rods and rings?

This image of mouse embryonic fibroblasts comes from Cara Schiavon, a graduate student in Rick Kahn’s lab in the Department of Biochemistry. It was impressive enough to capture interest from Emory Medicine‘s graphics designer Peta Westmaas. The light green shapes are “Rods and Rings,” structures that were identified just a few years ago by scientists studying how cells respond to antiviral drugs, such as those used against hepatitis C.

The rod and ring structures appear to contain enzymes that cells use for synthesizing DNA building blocks. Patients treated with some antiviral drugs develop antibodies against these enzymes.

The turquoise color represents microtubules, components of cells’ internal skeletons. The orange color shows DNA within nuclei. The spots in the nuclei are areas where DNA is more compact. The overall image is a “z-stack projection” acquired using the Olympus FV1000 confocal microscope in Emory’s Integrated Cellular Imaging Core.

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Toe in the water for Emory cryo-EM structures

Congratulations to Christine Dunham and colleagues in the Department of Biochemistry for their first cryo-electron microscopy paper, recently published in the journal Structure.

The paper solves the structure of a bacterial ribosome bound to a messenger RNA containing a loop that regulates translation. This process is important for the study of several neurological diseases such as fragile X syndrome, for example.

Christine Dunham, PhD

Dunham writes: “We are focusing on establishing this in bacteria to understand frameshifting and protein folding as a consequence of codon preference. We will then build up our knowledge to potentially study eukaryotic translational control.”

The paper neatly links up with two Nobel Prizes: the 2017 Chemistry prize for cryo-electron microscopy and the 2009 Chemistry prize for ribosome structure, awarded in part to Dunham’s mentor Venki Ramakrishnan. Also, see this 2015 feature from Nature’s Ewen Callaway outlining how cryo-EM is a must have for structural biologists wanting to probe large molecules that are difficult to crystallize.

Construction now underway in the Biochemistry Connector will allow installation of microscopes (worth $6 million) necessary for Dunham and others to do cryo-EM here at Emory, although she advises that it will be several months until they are photo-op ready. For the Structure paper, Dunham collaborated with George Skiniotis at University of Michigan; he recently moved to Stanford. Read more

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Biomedical career fair April 13

We learned about this from Tami Hutto at BEST (Broadening Experiences in Scientific Training) and Maria Thacker Goethe at Georgia Bio . We will provide more information when it is available. Friday, April 13. Emory Conference Center + Hotel, 1615 Clifton.

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Five hot projects at Emory in 2017

CRISPR-Cas9 gene editing alleviates Huntington’s in mouse model

— Shi-Hua and Xiao-Jiang Li. This project is progressing, with funding from NCATS and a pig-oriented collaboration with partners in China.

Once activated by cancer immunotherapy drugs, T cells still need fuel (CD28)

— Rafi Ahmed’s lab at Emory Vaccine Center. Also see T cell revival predicts lung cancer outcomes. At Thursday’s Winship symposium on cancer immunotherapy, Rafi said the name of the game is now combinations, with an especially good one being PD-1 inhibitors plus IL2.

Pilot study shows direct amygdala stimulation can enhance human memory

— Cory Inman, Joe Manns, Jon Willie. Effects being optimized, see SFN abstract.

Immune responses of five returning travelers infected by Zika virus

— Lilin Lai, Mark Mulligan. Covered here, Emory Hope Clinic and Baylor have data from more patients.

Frog slime kills flu virus

— Joshy Jacob’s lab at Emory Vaccine Center. A follow-up peptide with a name referencing Star Wars is coming.

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Shaking up thermostable proteins

Imagine a shaker table, where kids can assemble a structure out of LEGO bricks and then subject it to a simulated earthquake. The objective is to design the most stable structure.

Biochemists face a similar task when they are attempting to design thermostable proteins, with heat analogous to shaking. Thermostable proteins, which do not become unfolded/denatured at high temperatures, are valuable for industrial processes.

Now imagine that these stable structures have to also perform a function. This is the two-part challenge of designing thermostable proteins. They have to maintain their physical structure, and continue to perform their function adequately, all at high temperatures. 

Eric Ortlund and colleagues, working with Eric Gaucher at Georgia Tech*, have a new paper published in Structure, in which they examine different ways to achieve this goal in a component of the protein synthesis machinery, EF-Tu. This protein exists in both mesophilic bacteria, which live at around human body temperature, and thermophilic organisms (think: hot springs).

A previous analysis by Gaucher used the ASR technique (ancestral sequence reconstruction) to resurrect ancient, extinct EF-Tus and characterize them. It was shown that that ancestral EF-Tus were thermostable and functional. EF-Tu’s thermostability declined along with the environmental temperature; ancestral bacteria started off living in hot environments and those environments cooled off over millions of years.

In the new paper, Ortlund and first author Denise Okafor show that stable proteins generated by protein engineering methods do not always retain their functional capabilities. However, the ASR technique has a unique advantage, Ortlund says. By accounting for the evolutionary history of the protein, it preserves the natural motions required for normal protein function. Their results suggest that ASR could be used to engineer thermostability in other proteins besides EF-Tu.

*Gaucher recently moved to Georgia State.

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