Mysterious DNA modification important in fly brain

Drosophila, despite being a useful genetic model of development, have very little DNA methylation on C. What they do have is methylation on A (technically, N6-methyladenine), although little was known about what this modification did for Read more

Where it hurts matters in the gut

What part of the intestine is problematic matters more than inflammatory bowel disease subtype (Crohn’s vs ulcerative colitis), when it comes to genetic activity signatures in pediatric Read more

Overcoming cisplatin resistance

Cisplatin was known to damage DNA and to unleash reactive oxygen species, but the interaction between cisplatin and Mek1/cRaf had not been observed Read more

David Lambeth

Antioxidants are no panacea

Derek Lowe, a respected science blogger and drug discovery expert who was blogging when this writer was still working in the laboratory, today has a roundup of a concept that anyone hanging around Emory might have clued into already.

Namely, antioxidants aren’t all they’re cracked up to be. Judging from the messages Gafas Ray Ban outlet to shoppers in the supermarket vitamin aisle, everybody needs more antioxidants. But evidence is accumulating that in some situations, antioxidants can be harmful: negating the adaptive effects of exercise on muscle tissue or even encouraging tumor growth, Lowe writes.

At Emory, Dean Jones has been patiently explaining for years that cells are not simply big bags with free radicals, thiols and antioxidants sloshing around indiscriminately. Instead, cells and oxidation-sensitive components are highly compartmentalized. Take for example, this recent paper in Molecular & Cellular Proteomics from Jones and Young-mi Go. Two major antioxidant systems in cells, glutathione and thioredoxin, function distinctly and independently, they show.

In a related vein, Kathy Griendling’s and David Lambeth’s labs were at the center of the discovery that reactive oxygen species are not only poisons that overflow from mitochondria, but important signals involved in many aspects of cell biology.

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Scientists identify trigger for glowing plankton

Have you ever waded or paddled through ocean water in dim light, and found that your actions caused the water to light up?

Susan Smith, PhD

Single-celled plankton called dinoflagellates are responsible for this phenomenon. Almost 40 years ago, scientists studying bioluminescence (light emitted by living things) proposed a mechanism by which physical deformation of the cell could lead to a trigger of the flash.

Susan M.E. Smith, a research assistant professor in David Lambeth’s laboratory in Emory’s Department of Pathology and Laboratory Medicine, recently was first author on a paper in PNAS identifying a molecule that scientists have long believed to be the key to this mechanism. The paper is the result of a collaboration with Tom DeCoursey’s laboratory at Rush University in Chicago.

The mechanism for the trigger, first envisioned by co-author Woody Hastings, works like this. It is known that acidic conditions activate luciferase, the enzyme that generates the light. Part of the dinoflagellate cell, the vacuole, is about as acidic as orange juice. Normally the acidity within the vacuole is kept separate from the luciferase, which is found in pockets on the outside of the vacuole called scintillons.

Proton channels are needed to trigger bioluminescence. Illustration courtesy of the National Science Foundation, which supported Smith's research

Now something is needed to let acidity (that is, protons) pass from the vacuole to the scintillons. That something is a proton channel: a protein that acts as a gate in the membrane, opening in response to electrical changes in the cell. Smith and her collaborators identified a proton channel called kHV1 that has unique properties: it lets protons flow in the right direction for the trigger to work! They studied kHV1 by inserting the dinoflagellate gene that encodes it into mammalian cells and probing its electrochemical properties, which are distinct from other proton channels.

The authors write: “Whereas other proton channels apparently evolved to extrude acid from cells, kHV1 seems to be optimized to enable proton influx.”

The gene they found actually comes from a type of dinoflagellate that does not flash: K. veneficum, which feeds on algae and sometimes forms harmful blooms that kill fish. They propose that it uses acid influx to aid in capturing or digesting its prey.

“Hastings’ prediction led us to look for this kind of channel, we found it in a related organism, and it had the right properties to fit the prediction,” Smith says, and adds that her team has since found a similar gene in flashing dinoflagellates. She says studying the proton channel may give clues to ways to control harmful dinoflagellates, as well as help scientists understand how plankton respond to greater ocean acidity.

Proton channels are found in humans too. In fact, the same kind of molecule that triggers plankton flashing in the ocean helps human white blood cells produce a bacteria-killing burst of bleach. They are also involved in allergic reactions and in sperm maturation.

Smith is co-author on a paper that is in the journal Nature this week, exploring the selectivity of the human version of kHV1. Smith says that her interest in proton channels grew out of her work on Nox enzymes (which produce the bacteria-killing bleach) with Lambeth.

“I got interested in the proton channel because its function is necessary for peak Nox performance in human phagocytes. We started a little side project on the human proton channel that kind of blossomed,” she says. Her collaboration with DeCoursey uses “evolutionary information to get at the function of these channels in general.”

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How to build a distinguished career studying vascular biology

Kathy Griendling, PhD (in green), surrounded by members of her lab

On June 15, 2010, vascular biologist Kathy Griendling delivered the 2010 Dean’s Distinguished Faculty lecture at Emory University School of Medicine.

Some of Griendling’s publications have been cited thousands of times by fellow scientists around the world, making her the lead member of a small group of researchers at Emory called the “Millipub Club.”

With her five children and one grandson watching in the back row, Griendling explained how she and her colleagues, over the course of more than two decades at Emory, have gradually revealed the functions of a family of enzymes called NADPH oxidases in vascular smooth muscle cells. Read more

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Serendipity & strategy: Nox researcher David Lambeth

David Lambeth, MD, PhD, with one of his paintings

David Lambeth, MD, PhD, with one of his paintings

NADPH oxidases (Nox for short) are enzymes that help plants fight off pathogens, guide sexual development in fungi, are essential for egg laying in flies and even help humans to sense gravity.

But what first attracted the interest of Emory researchers was the role of Nox in vascular disease and cancer. Along with Emory cardiologist Kathy Griendling, pathologist David Lambeth pioneered the discovery of how important these reactive oxygen-generating enzymes really are.

Lambeth will be honored this month in San Francisco by the Society for Free Radical Biology and Medicine with their 2009 Discovery Award. A profile in Emory Report explores his musical and artistic pursuits as well as his science.

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