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Los Alamos National Laboratory Research Quarterly, Winter 2003
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Dateline Los Alamos

Healing or Self-Damage:
Immunoreceptors' "Split Personality"

Sometimes described as a "liquid brain," the immune system is continually poised at the edge of disaster, required to aggressively attack invading pathogens without damaging its own body. The challenge of understanding the complexity of signaling entailed in such a delicately balanced system has been taken up by Laboratory researchers, who are developing a mathematical model of immunoreceptors, a large and diverse group of proteins that decode regulatory signals.

As recently reported in Molecular Immunology, a team led by Byron Goldstein of T-10 (Theoretical Biology and Biophysics), and including Michael Blinov, Jim Faeder, Bill Hlavacek, Antonio Redondo, and Carla Wofsy, is studying the Fc epsilon receptor. This receptor is a mast-cell membrane protein that normally functions in inflammation to help remove pathogenic organisms but which, when regulation goes awry, serves as a signaling intermediary in allergic reactions. The receptor binds the IgE class of antibodies and is activated when foreign substances (antigens) bind to those antibodies. Receptor activation initiates a cascade of biochemical changes that culminates in the secretion of histamine and other inflammatory biochemicals. In allergic reactions, the inflammatory process becomes excessive, leading to discomfort (as in hay fever) or even to death by asphyxiation (as in extreme insect-sting reactions).

By creating and studying a mathematical model of this signaling cascade, the investigators hope to understand the behavior of the signaling system as a whole. In the process, they should also be able to glean more insight into the complex subcellular networks that regulate this form of receptor-mediated signaling. As emphasized by Faeder, "Signaling has been thought of as a linear chain of events, but it's not like that at all."

The investigators hope to expand the model to include additional components of the signaling cascade. Another goal is to find reduced models that encompass only the key biochemical interactions in this cascade to make it easier for experimentalists to identify critical points for potential drug treatments. Currently available drugs like antihistamines and ibuprofen tend to intervene after the fact, that is, after this signaling cascade has run its course, and therefore relieve symptoms rather than address causes.

"A detailed mathematical model of a signaling cascade for an immune system receptor has never been done before," adds Goldstein. "What's amazing is that as complicated as the system is, our model works. It's consistent with a wide array of experimental observations." This, of course, is potentially good news for allergy sufferers, since researchers may some day be able to use the findings of this model to design more efficacious medications that intervene in the allergic process at an earlier stage.—Kevin N. Roark and Vin LoPresti


Improving Meteor Impact Predictions

An array of infrasound detectors used by the Laboratory to "listen" for clandestine nuclear tests has played a key role in helping scientists more accurately determine how often Earth is hammered by giant meteors like the one that flattened 1,900 square miles of forest in Tunguska, Siberia, in 1908. Previously, scientists believed that very large meteors like the Tunguska one entered Earth's atmosphere every 200 to 300 years. Now, Lab researcher Douglas ReVelle and his colleagues have collected evidence that such catastrophic meteor strikes occur less frequently—about every 1,000 years. Their findings were published in the November 21 issue of Nature.

ReVelle teamed up with researchers from Sandia National Laboratories, the University of Western Ontario, ET Space Systems, and the U.S. Space Command to look at both infrasound and light signatures from mid-size meteors that entered Earth's atmosphere over the last eight years. When such meteors—ranging from 3 to 30 feet in diameter—plunge into the atmosphere, they explode, creating a brilliant flash of light and a blast equivalent to many kilotons of TNT.

Because their arrival is heralded by a fireball and a burst of shock-induced sound waves below the range of human hearing, the meteors are easily detected by satellites that look for flashes from incoming missiles or nuclear blasts and by the Lab's infrasound arrays, which are tuned to detect ultralow-frequency and very small amplitude waves. Typical amplitudes are only one-millionth those of normal sea-level atmospheric pressure readings. The satellite and infrasound systems were designed to detect clandestine nuclear weapons tests and other military activities. ReVelle and his colleagues, however, discovered that by combining the optical and infrasonic data, they could also more precisely calculate the size and energy of large incoming meteors.

The team examined optical data for 300 meteors that "exploded" in Earth's atmosphere between 1994 and 2002. From those data, they evaluated the meteors' total optical energy and converted that energy into an equivalent impact energy. As part of their conversion work, they calibrated the optical data with independent source-energy estimates for a dozen well-observed, large meteors. Most of these estimates came from data from the Los Alamos infrasound arrays. Funded by the Department of Energy, the Earth and Environmental Sciences Division operates five infrasound arrays across the western United States that routinely monitor and locate global atmospheric explosions.

From the satellite and infrasound analyses, ReVelle produced a graph that relates the number of meteors colliding with Earth in a year to their impact energy and corresponding size. Over twelve magnitudes of energy, a single distribution fits the data from mid-size meteors to giants like the one that leveled the Tunguska forest.

"What is exciting about this work for me is that without the data from Los Alamos' infrasound arrays, this probably would not have been possible," said ReVelle. "Infrasound provided the key to unraveling the source energy of 75 percent of these collision events."

In addition to providing impact estimates for large meteors, the team's work also holds promise for accurately distinguishing between meteoric fireballs and other atmospheric phenomena, such as volcanic eruptions, accidental explosions, and incoming missiles. Combining satellite and infrasound data offers a means of definitively identifying such events, a capability that could prove critical during times of heightened regional or global tension.—James Rickman

 

 

A mast cell with IgE antibodies bound to the Fc receptors on its surface

A mast cell with IgE antibodies bound to the Fc receptors on its surface; when a foreign substance binds to those antibodies, the Fc-receptor signaling cascade is triggered and inflammatory biochemicals such as histamine are secreted. When the secretions become excessive, the foreign substance is termed an "allergen."

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Two infrasound microphones under white heat shields (about 2 feet tall).

Two infrasound microphones under white heat shields (about 2 feet tall). The black "wires" in the foreground are porous hoses that reduce wind noise for the microphones.

 
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