Wednesday, February 2, 2011

DEEP SLEEP IN BIRDS

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When we are asleep, those regions of our brain that were particularly active during wakefulness sleep more deeply. Researchers at the Max Planck Institute for Ornithology in Seewiesen, Germany and colleagues have demonstrated for the first time that this is also the case in birds.

The researchers prevented pigeons from taking their afternoon nap by showing them David Attenborough’s nature documentary series The Life of Birds. An eye cap temporarily covered one eye during the movie session. During the following night, the researchers observed deeper sleep in the part of the brain neurologically connected to the stimulated eye compared with the same region in the other brain hemisphere. A non-visual region did not show such an asymmetry in sleep.

Birds are the only animals outside of mammals whose sleep is also divided into a deep sleep phase, the so-called “Slow Wave Sleep” (SWS) and a dream phase, REM sleep (“Rapid Eye Movement Sleep”). During SWS sleep the brain generates strong electrical signals which are manifested as high-amplitude low-frequency waves in the electroencephalogram (EEG).

In mammals, the intensity of SWS increases and decreases as a function of prior time spent awake and asleep, respectively. This was now also shown for the first time in birds by researchers of the “Sleep and Flight”- Research Group at the Max Planck Institute of Ornithology in Seewiesen. Pigeons prevented from taking their normal afternoon naps slept more intensely at night. This suggests that birds respond to sleep deprivation in a manner similar to mammals, including us humans.
The local aspect of sleep

The new findings indicate that the similarity of mammalian and avian sleep seems to go even further. In both, sleep intensity depends on prior brain use during wakefulness. The researchers stimulated the visual processing region of one hemisphere of the pigeon brain by showing the birds David Attenborough’s nature documentary The Life of Birds while orientating one eye toward the film and capping the other. The videos were played continuously for eight hours during the day, and the researchers gently stimulated the birds to stay awake whenever they fell asleep. During the following night, the researchers measured sleep intensity in the visual processing regions of both hemispheres and compared them with other, non-visual regions.

As in mammals, the stimulated region showed more intense sleep than its counterpart in the other hemisphere. A non-visual region did not show this asymmetric effect in sleep intensity. “We observed mammal-like ‘local sleep’ in birds. It is therefore most likely that the main function of slow wave sleep is brain restoration", says John Lesku, first author of the study.

(Photo: © Michael Gehrisch/John Lesku)

Max Planck Institute

PUTTING UP A STRUGGLE AGAINST CANCER

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MIT scientists have discovered that cells lining the blood vessels secrete molecules that suppress tumor growth and keep cancer cells from invading other tissues, a finding that could lead to a new way to treat cancer.

Elazer Edelman, professor in the MIT-Harvard Division of Health Sciences and Technology (HST), says that implanting such cells adjacent to a patient’s tumor could shrink a tumor or prevent it from growing back or spreading further after surgery or chemotherapy. He has already tested such an implant in mice, and MIT has licensed the technology to Pervasis Therapeutics, Inc., which plans to test it in humans.

Edelman describes the work, which appears in the Jan. 19 issue of the journal Science Translational Medicine, as a “paradigm shift” that could fundamentally change how cancer is understood and treated. “This is a cancer therapy that could be used alone or with chemotherapy radiation or surgery, but without adding any devastating side effects,” he says.

Cells that line the blood vessels, known as endothelial cells, were once thought to serve primarily as structural gates, regulating delivery of blood to and from tissues. However, they are now known to be much more active. In the 1980s, scientists discovered that endothelial cells control the constriction and dilation of blood vessels, and in the early 1990s, Edelman and his postdoctoral advisor, Morris Karnovsky, and others, discovered an even more important role for endothelial cells: They regulate blood clotting, tissue repair, inflammation and scarring, by releasing molecules such as cytokines (small proteins that carry messages between cells) and large sugar-protein complexes.

Many vascular diseases, notably atherosclerosis, originate with endothelial cells. For example, when a blood vessel is injured by cholesterol, inappropriately high blood sugar, or even physical stimuli, endothelial cells may overreact and provoke uncontrolled inflammation, which can further damage the surrounding tissue.

Edelman and HST graduate student Joseph Franses hypothesized that endothelial cells might also play a role in controlling cancer behavior, because blood vessels are so closely entwined with tumors. It was already known that other types of cells within tumors, known collectively as the tumor stromal microenvironment, influence cancer cell growth and metastasis, but little was known about how endothelial cells might be similarly involved.

In the new study, Edelman, Franses and former MIT postdoctoral fellows Aaron Baker and Vipul Chitalia showed that secretions from endothelial cells inhibit the growth and invasiveness of tumor cells, both in cells grown in the lab and in mice. Endothelial cells secrete hundreds of biochemicals, many of which may be involved in this process, but the researchers identified two that are particularly important: a large sugar-protein complex called perlecan, and a cytokine called interleukin-6. When endothelial cells secrete large amounts of perlecan but little IL-6 they are effective at suppressing cancer cell invasion, whereas they are ineffective in the opposite proportions.

The researchers theorize that there is a constant struggle between cancer cells and endothelial cells, and most of the time, the endothelial cells triumph. “All of us, every day, are exposed to factors that cause cancer, but relatively few of us exhibit disease,” says Edelman. “We believe that the body’s control mechanism wins out the bulk of the time, but when the balance of power is reversed cancer dominates.”

The struggle also depends on a third player, the endothelial cells’ extracellular matrix — structural proteins that pave blood vessels and on which the endothelial cells reside. Endothelial cells only function properly when their extracellular matrix is stable and of the correct biochemical composition. Under normal conditions, if a cell becomes cancerous, the endothelial cell may then keep it in check. However, the cancer cell fights back by trying to destroy the extracellular matrix or change the endothelial cell directly, both of which hinder the endothelial cell’s efforts to control the cancer.

“There is this three-way balance that needs to be achieved,” says Edelman. The more aggressive a cancer cell, the more likely it is to overcome the endothelial cells and extracellular matrix, allowing it to spread to other tissues.

Jack Lawler, professor of pathology at Harvard Medical School, says the new work “opens the door to many avenues” of future research. “The history of cancer research has really focused on tumor suppressor genes and oncogenes as the sole effectors of cancer.” While attention has turned to other cell types in the past 15 years, “the endothelial cell, for the most part, has not been considered in that context,” says Lawler, who was not part of the research team.

Several years ago, Edelman began using endothelial cells, grown within a scaffold made of denatured, compressed collagen (a protein that makes up much of human connective tissue), as an implantable device. The “matrix-embedded endothelial cells” served as a convenient unit that could be produced in bulk, tested for quality control, retained intact for months and implanted immediately when needed. This way, the healthiest cells could be selected to secrete all of the chemicals normally released by endothelial cells and placed in multiple locations in the body to control disease.

In clinical trials these implants were placed around blood vessels after vascular surgery and controlled local clotting and infection better than devices without cells. Significantly, because the endothelial cells were associated with a matrix mimicking their natural state, even cells from other people could be implanted without being rejected by the patients’ immune systems. No major side effects were seen in the clinical trials.

“Blood vessels and endothelial cells are the perfect regulatory units and our synthetic device recapitulated these control units perfectly,” says Franses. Blood vessels penetrate to the deepest recesses of tumors, and in doing so carry the powerful regulatory endothelial cells as close to cancer cells as possible. The extracellular matrix backbone of the vessels can keep the endothelial cells healthy and the healthy endothelial cells control nearby cancer cells. “This is what we mimicked with our devices,” he says. “In a sense it is like putting a cellular policeman on the corner of every tumor neighborhood.”

In one mouse experiment reported in the new paper, endothelial cell implants significantly slowed tumor growth and prevented gross destructive change in tumor structure. Another experiment showed that cancer cells that had been grown in the secretions of endothelial cells were less able than standard cancer cells to metastasize and colonize the lungs of mice.

The new findings could also explain why drugs that suppress angiogenesis — growth of new blood vessels — have shown only transient and moderate benefit for cancer patients thus far. “You starve the tumor of its blood supply, but you also damage tumor blood vessel endothelial cells, so when the tumor comes back, there’s nothing to keep it in check. The vessels feed the tumor but their endothelial cells control the cancer cells within. Giving the endothelial cells without the blood vessels provides the best of both worlds and perhaps one day could provide new means of cancer therapy,” says Edelman.

(Photo: Joseph Franses)

MIT

HOW LIQUIDS BEHAVE

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In a finding that has been met with surprise and some controversy in the scientific community, researchers at MIT and elsewhere have discovered a basic property that governs the way water and many other liquids behave as their temperature changes.

Liquids have long been known to exhibit a rapid change in properties near a point called the glass transition temperature, where the viscosity of the liquid — its “thickness,” or resistance to flow — becomes very large. But MIT professor Sow-Hsin Chen and his co-researchers have found a different transition point at a temperature about 20 to 30 percent higher, which they call the dynamic crossover temperature. This temperature may be at least as important as the glass transition temperature, and the viscosity at the dynamic crossover temperature seems to have a universal value for a large class of liquids (called glass-forming liquids) that includes such familiar substances as water, ammonia and benzene.

At this new transition temperature, “all the transport properties of the liquid state change drastically,” Chen says. “Nobody realized this universal property of liquids before.” The work, carried out by physics professor Francesco Mallamace of the University of Messina, Italy (who is a research affiliate at MIT) and four of his students from Messina, along with Chen, an MIT professor emeritus of nuclear science and engineering, and Eugene Stanley, a physics professor at Boston University, was published on Dec. 28 in the Proceedings of the National Academy of Sciences.

This is very basic research and Chen says it is too early to predict what practical applications this knowledge could produce. “We can only speculate,” he says, because “this is so new that real practical applications haven’t really surfaced.” But he points out that one of the most widely used building materials in the world, concrete, flows as a liquid-like cement paste during construction, and a better ability to understand its process of transition to solid form might be significant for improving its durability or other characteristics.

The team had previously published their findings about the new transition temperature in water, but the new work extends this to the whole class of liquids. While the findings remain somewhat controversial, Chen says that last month an international symposium devoted to the study of this phenomenon was held in Florence, Italy involving about 50 scientists from various nations.

Benjamin Widom, an emeritus professor of chemistry at Cornell University, says that the researchers’ demonstration of the universality of this crossover phenomenon and the fact that the liquids studied all show roughly the same level of viscosity at their crossover point “is striking,” and adds that “These observations are certain to arouse much interest among those who work in the field, and perhaps even controversy because they contradict long-accepted ideas.”

Liquids become much more viscous as they approach their freezing temperature — that is, they begin to move less like water and more like honey. But the exact progression of this transition is difficult to measure, so the details are still poorly understood. The new research draws on published studies detailing the behavior of 84 different liquids, and the researchers found that a fresh analysis of the data, along with their own experimental work on water, shows a previously unrecognized universal property they all share in terms of how their viscosity and other characteristics change with temperature.

“Measuring viscosity is a very tedious process,” Chen says, and measuring how it changes over tiny increments of temperature is even more difficult. But Chen and his colleagues found that they were able to measure relaxation time of water — which is directly proportional to its viscosity — using a state-of-the-art instrument at the National Institute of Standards and Technology in Washington that shoots neutrons at the material. “We discovered we can measure relaxation time very effectively with this instrument,” Chen said, and they have been carrying out such measurements over the last several years.

(Photo: MIT)

MIT

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