Computing with bubbles, why hemorrhagic fever viruses are so bad, and how fat cells get fatter

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Bubbles encode information

Electrons racing through circuits form the heart of today’s computers. Bubbles of gas could also serve as bits of information, performing all the basic steps needed for computation, according to a new paper in Science from MIT.

Manu Prakash and Neil Gershenfeld at MIT’s Center for Bits and Atoms created lab-on-a-chip systems where bubbles of nitrogen gas course through tiny water channels. Because the concentration of bubbles in a channel affects how quickly the fluid flows through it, the researchers were able to control how the bubbles moved through intersections of those channels. By precisely shaping those intersections, the researchers got them to perform like logic gates.

These gates sorted the bubbles, sending them down one path or another, depending on how the bubbles encountered each other at these crossroads. For example, if two bubbles met at an intersection designed to work as an “AND” logic gate, the bubbles joined together and traveled down one of two channels. The researchers were able to join these gates in more complex combinations, making a so-called ring oscillator, for example, that could keep time (see photo).

A bubble computer

(Credit: Felice Frankel and Manu Prakash, MIT)

Another local group, led by George Whitesides at Harvard, demonstrated, in the same issue of Science, a similar system to encode information using water droplets flowing through small channels of an oily liquid.

These liquid computers aren’t likely to replace our laptops, but they could be useful for programming lab-on-a-chip systems to do much more complex reactions, the researchers say. Mason Inman

Viruses sneak into cells on iron receptor

Hemorrhagic fever viruses cause gruesome and often fatal infections marked by uncontrolled bleeding throughout the body. While they are more commonly associated with Africa (Ebola being the most well known type), one family of the viruses pops up sporadically in South America, passing from rodents to humans to cause Bolivian, Argentine, Venezuelan, and Brazilian hemorrhagic fever.

In this week’s online edition of Nature, Hyeryun Choe and coworkers from Children’s Hospital and Harvard Medical School report that these viruses enter cells by hitching a ride on a protein, the transferrin receptor, that sits on the cell surface and transports iron into the cell. This route differs from that taken by the related Lassa virus from Africa, and opens up new opportunities for better treatment of infection.

The presence of the receptor in the lining of blood vessels could explain the bleeding and organ damage that comes with infection. And its abundance in activated immune cells could be one reason why the immune system is so helpless in fighting the infection.

An antibody specific for the transferrin receptor blocked viruses from entering cells, suggesting an immediate approach to treatment. Several transferrin receptor antibodies have been developed as possible anticancer agents and the investigators are planning to test these soon. Pat McCaffrey

Lean mice reveal new regulator of fat production

An enzyme that drives the early stages of fat cell maturation could provide a new target for antiobesity drugs.

The enzyme, xanthine oxidoreductase (XOR), is well known for its role in producing metabolic byproducts that cause the painful condition known as gout. Now, work from Jeffrey Flier and colleagues at the Beth Israel Deaconess Medical Center, with collaborators at Rockefeller University in New York, has uncovered an unsuspected role for XOR in the development of obesity.

The investigators showed that XOR activates a master gene regulator that signals cells to begin storing fat. Blocking the process could provide early intervention for obesity, stopping fat before it forms. The researchers found that obese mice had high levels of the enzyme, while mice lacking the protein had half the fat of their normal counterparts.

The byproducts of XOR not only cause gout but also contribute to the production of artery-clogging fats. The new work could explain why gout and heart disease often occur with obesity.

An XOR inhibitor commonly used to treat gout did not reduce fat cell maturation in cell culture. However, the investigators identified a different inhibitor that could. XOR inhibitors should be tested for their effects on body weight, they conclude.

The research appears in Cell Metabolism. Pat McCaffrey

Decoding the past from cave rocks, spying on sickly mice, and pinpointing the cause of diabetic blindness

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Stalagmite study tells a story of past storms

When studying climate patterns of the past, geoscientists often look at samples of ice cores, soil, and tree rings. Now, a Boston College researcher and colleagues have found that stalagmites from caves can also offer a detailed look into the past. The stalagmites preserve an accurate record of individual storms and could provide much needed data to help resolve the controversy over the possible link between climate change and hurricane intensity.

In a paper in this month’s Geology, Amy Benoit Frappier of Boston College and colleagues show that chemical analysis of a stalagmite from a cave in Belize revealed a record of the storms in the region from 1977 to 2000. A stalagmite is formed when minerals crystallize out of water that has seeped into the cave. Over time, the stalagmite slowly grows wider, layer by layer, forming rings like a tree.

It’s known that an isotope of oxygen, oxygen-18, is present at lower levels in rainwater from tropical cyclones. So the researchers measured the levels of this isotope in microsamples taken from the various layers of the stalagmite. They found that they could see the effects of individual storms with a resolution of a couple weeks’ time. (Earlier measurements from stalagmites had a time resolution of decades or more.)

Each cyclone caused an abrupt drop in the amount of oxygen-18 in a specific layer of the stalagmite. When they compared their data with storm records from the region, they found that the magnitude of the decrease in oxygen-18 levels was strongly linked to the intensity of the storm.

The researchers say that measurements from older stalagmites could provide a long-term record of storms, potentially stretching back a million years or more, which could help settle the debate about the influence of global warming on storm intensity. Mason Inman

Constant surveillance reveals the secret lives of lab mice

The mice in Susan Lindquist’s lab at the Whitehead Institute may be forgiven for feeling a little paranoid—someone is watching them all the time.

Researchers videotaped the animals 24 hours a day to see if they could detect signs of neurodegenerative disease earlier or even spot new ones. Lindquist and colleagues developed software that automatically classifies and tallies up the mouse movements according to categories like resting, walking, running, jumping, or hanging upside down.

The animals under watch had a neurodegenerative prion disease or the mouse equivalent of Huntington’s disease. In most labs, researchers observe mice when put through their paces in mazes and swimming pools, or using special exercise equipment. But such tests are just snapshots of the animal’s behavior, the researchers write, which can be highly variable and may not allow researchers to detect subtle changes.

Continuous monitoring of animals in their cages, on the other hand, revealed known habits associated with brain-wasting disease at an earlier age than previously observed. For example, the mice models for Huntington’s spent less time hanging, jumping, or stretching in their cages. Some behaviors seen in the mice with prion disease had never been observed before: increased walking, sniffing, and jumping.

This new kind of behavioral profiling could be useful for evaluating the effects of experimental therapies in animals or for behavioral analysis in large-scale mouse genetics projects, the researchers write in this week’s Proceedings of the National Academy of Sciences. Pat McCaffrey

Protein analysis of human eyeball fluid uncovers possible cause of diabetic eye damage

More than half of diabetics eventually go blind from malfunctioning blood vessels that feed the retina, the light-sensitive tissue at the back of the eye. Leaks in the vessels lead to swelling of the retina, which destroys vision.

In analyzing proteins from the eye, researchers from the Joslin Diabetes Center have found a new culprit in retinal swelling. Their results, published in Nature Medicine, also suggest that the same protein is involved in the brain swelling that occurs after stroke or head injury. Targeting the protein, an enzyme called carbonic anhydrase could lead to new treatments for these conditions.

Edward Feener and colleagues collected vitreous, the gel-like fluid that fills the eyeball and bathes the retina, from 25 people during eye surgery. Using proteomics methods, they identified 117 proteins in the fluid.

In people with diabetic retinopathy, they found that carbonic anhydrase was up to 15 times more abundant compared to nondiabetics.

When the investigators injected the protein into rat vitreous, it caused a rapid increase in blood vessel leakage and swelling of the retina. They found that in the rat eye, carbonic anhydrase was involved in regulating vessel permeability.

The investigators showed that blocking either the enzyme or its downstream effectors prevented the changes. And when they injected the protein into rat brain, it caused vascular leakage there, too. Pat McCaffrey

Turning on a cancer-control switch, predicting drug resistance in a flu pandemic, and the hunt for missing supernovae dust

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Restoring gene function reverses cancer’s course

Many cancers get their start when the critical tumor suppressor gene, p53, is turned off, setting off a cascade of events in the cell that results in unrestrained growth. Now, in a study from Nature this week, local researchers have shown that restoring the function of the suppressor gene can reverse the process in mice, causing well-established tumors to melt away.

The results indicate that cancers depend on continuous inactivation of the p53 gene to thrive. And since reduced p53 activity is involved in half of all human cancers, methods to reactivate p53 by gene therapy or drug treatment could potentially treat many kinds of cancer.

Normally, the p53 protein keeps cancer at bay by triggering the death of damaged cells before they can grow out of control. The researchers, led by MIT’s Tyler Jacks, genetically engineered mice with a reversible mutation in the p53 gene. With the gene switched off, the mice developed lymphomas and sarcomas. Once they switched the gene on, the tumors disappeared.

This computer-generated 3-D image (based on MRI data) shows an abdominal lymphoma (tumor in red) in a mouse before (left) and 12 days after (right) p53 reactivation. (Credit: Tyler Jacks, Jan Grimm, and colleagues.)

Different cancer types responded differently to p53 reactivation—in lymphoma cells, p53 rapidly triggered cell suicide within just a few days. Sarcoma tumors died more slowly, over a period of weeks, because p53 slowed and then stopped cell division.

A related paper by New York researchers, also published in Nature this week, showed that p53 reactivation similarly inhibited the growth of liver cancer cells, which were then destroyed by the animal’s immune system.

Restoring the function of the p53 gene had no effect on the mouse’s normal tissues, suggesting that p53-based therapies may avoid some of the side effects of traditional cancer treatments such as chemotherapy. Pat McCaffrey

Drug-resistant viruses could spread with flu

Unlike the last flu pandemic, the response to the next one will feature heavy use of antiviral drugs, mainly oseltamivir (Tamiflu). Governments are stockpiling the drugs in anticipation of a major outbreak, but there’s been little public discussion about the problem of resistance that will surely emerge once the drugs are widely used.

In a paper this week in PLoS Medicine, Harvard School of Public Health researcher Marc Lipsitch and colleagues report the results of computer modeling of the impact of drug-resistant flu strains in a worldwide epidemic.

Their results predict that resistant viruses will spread quickly in response to drug use, and their proliferation will reduce the effectiveness of the treatments. Using antiviral drugs will still help delay the spread of the pandemic and reduce its size, though not as effectively as currently predicted. This delay is critical to give extra time for vaccine production in the early stages of the pandemic.

The theoretical scenario makes assumptions about the rates of viral spread, the extent of drug use, and the implementation of other measures like quarantines, school closings, and limits on travel.

One outstanding question is whether drug-resistant viruses will be weaker and less able to pass from person to person, a situation that could improve the effects of therapy.

The bottom line, according to the researchers, is that future planning efforts will need to consider the risk of resistance, and establish procedures for monitoring its emergence during an actual outbreak. Pat McCaffrey

Supernova remnants are missing their halos

When stars blow up in massive explosions called supernovas, much of the star’s mass billows out in a huge cloud, while the center often collapses to form a new star. Astrophysicists have long believed that these new stars are surrounded by a disk of dust.

But a search for these “fallback disks,” using ground telescopes and an orbiting space telescope, has come up empty, according to a new study in the Astrophysical Journal from MIT.

Fallback disks would have implications for the fate of the new star. If the star’s gravity is sufficient to attract the dust, the star could gain enough mass to become a black hole. If the dust stays put, however, it could congeal to form new planets. But if no dust is present, new black holes or planets would be less likely to form than previously thought.

Current computer models of supernovas generally predict the creation of fallback disks, so with little evidence of their existence, astrophysicists may have to revisit their models. Mason Inman