ScienceWeek

SCIENCEWEEK

April 13, 2007

Vol. 11 - Number 14

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Science gains reality when it is viewed not as an abstraction, but as the concrete sum of work of scientists, past and present, living and dead. Not a statement in science, not an observation, not a thought exists in itself. Each was ground out of the harsh effort of some man, and unless you know the man and the world in which he worked; the assumptions he accepted as truths; the concepts he considered untenable; you cannot fully understand the statement or observation or thought.

-- Isaac Azimov (1920-1992)

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Contents (full text below):

1. Medicine: Light Hits the Liver

2. Planetary Science: As Tiny Worlds Turn

3. Climate Change: Global Warming Is Changing the World

4. Cell Biology: Autophagy and Cancer

5. Obituary: Knut Schmidt-Nielsen (1915–2007)

6. Solid-State Chemistry: Crystal tennis rackets

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1.

Science 13 April 2007: Vol. 316. no. 5822, pp. 206 - 207 DOI: 10.1126/science.1142238

Medicine: Light Hits the Liver

Göran K. Hansson

Atherosclerosis, the underlying cause of most cases of myocardial infarction, stroke, and gangrene, is the most common lethal disease in Western societies and is expected to become the number one killer globally by 2020 (1). It is an inflammatory disease triggered by the accumulation of plasma lipoproteins in the artery wall (2). In this scenario, lipids cause inflammation. However, a report by Lo et al. on page 285 in this issue (3) turns the situation upside-down by showing that two factors produced by immune cells--the cytokines lymphotoxin and LIGHT--cause the amount of lipids in the blood to increase.

Several studies have implicated the tumor necrosis factor superfamily of proinflammatory cytokines in lipid metabolism. Tumor necrosis factor was discovered not only as a soluble protein that induces the death of tumor cells but also as a molecule (cachectin) that causes hypertriglyceridemia and wasting of muscle and fat tissue (4). These effects are due to its inhibition of the enzyme lipoprotein lipase, thus limiting the supply of fatty acids for energy production and fat storage. These remarkable metabolic effects of this cytokine did not attract as much attention as its proinflammatory actions and its ability to promote cell death. However, recent findings of tumor necrosis factor secretion from adipose tissue of individuals with metabolic syndrome, a condition predisposing to atherosclerosis, have focused much interest on the metabolic action of this cytokine and its cousins (5).

Several of the more than 40 members of the tumor necrosis factor superfamily of proinflammatory molecules are soluble cytokines; others are membrane proteins that can ligate receptors on adjacent cells. There is substantial cross-talk between receptors and ligands. Two members of this family, lymphotoxin and LIGHT, share many features with tumor necrosis factor (the prototypic family member), such as promoting inflammation and host defense against pathogens, and they have been implicated in several inflammatory diseases, including rheumatoid arthritis and Crohn's disease (6). Two other superfamily members, CD40 and OX40L, are involved in atherosclerosis, and seem to propagate plaque inflammation (7, 8).

In contrast to tumor necrosis factor, LIGHT is mainly expressed on the surface of T cells and specialized cells of the immune system called dendritic cells (9). Lo et al. observed that transgenic mice engineered to overexpress LIGHT on T cells developed hyperlipidemia, displaying elevated cholesterol and triglyceride concentrations in the blood. When T cells from such mice were transferred into normal mice, plasma cholesterol concentration increased substantially. LIGHT (and lymphotoxin) bind to the lymphotoxin beta receptor but also to other receptors. By treating mice with soluble forms of the receptor, to function as "decoys," the authors establish that the hyperlipidemic effect of LIGHT depends on the lymphotoxin beta receptor.

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2.

Science 13 April 2007: Vol. 316. no. 5822, pp. 211 - 212 DOI: 10.1126/science.1141930

Planetary Science: As Tiny Worlds Turn

David P. Rubincam and Stephen J. Paddack

Sunlight changes the rotation rate of an asteroid? The idea seems absurd, but on page 272 Lowry et al. (1) and on page 274 Taylor et al. (2) report observations that indicate sunlight is doing just that to the small asteroid 2000 PH5, and Kaasalainen et al. indicate the same is happening on 1862 Apollo (3). The mechanism is the Yarkovsky-O'Keefe-Radzievskii-Paddack effect, mercifully shortened to YORP. With YORP now on a solid foundation, we may be able to understand a number of strange observations involving small spinning asteroids and asteroid binary systems.

The saga of sunlight changing into spin began with Ivan Yarkovsky, a Polish engineer who realized more than a century ago that the infrared radiation escaping a body warmed by sunlight carries off momentum as well as heat (4). Point this heat in the right direction, and it will function like a rocket motor: Each infrared photon escaping the object carries away momentum, thanks to the relationship p = E/c, where p is the photon's momentum, E is its energy, and c is the speed of light. By the principle of action-reaction, the object emitting the photon gets a kick in the opposite direction. (Yarkovsky knew nothing of photons and based his reasoning on the outmoded ether concept, but his idea survives the translation to modern physics.) Yarkovsky thrust is tiny, but space is so empty there is no friction to stop it. Moreover, because the Sun is always shining, the Yarkovsky effect goes on century after century with an inexhaustible supply of photonic fuel, profoundly altering the orbits of meter-sized meteoroids (5).

V. V. Radzievskii applied the photon thrust idea to rotation by imagining each face of a cubical meteoroid painted white on one half and black on the other; sunlight reflected by the white part pushes that area more than the black half, causing a torque, which changes the rotation rate (6). His mechanism is weak because the black half, although it reflects little, makes up much of the difference by emitting infrared photons. Moreover, most small solar system objects have fairly uniform albedoes (that is, the fraction of light reflected) across their surfaces.

Building on this work, John A. O'Keefe and one of us (S.J.P.) at NASA realized that shape was a much more effective means of altering a body's spin rate than albedo and set about measuring spin changes in the laboratory. The idea was that light reflecting off of various angled surfaces on the object could alter its rotation. Thus YORP was born.

O'Keefe and Paddack imagined a body shaped rather like that shown in the figure: two wedges glued to a sphere. As the object rotates, the Sun shines on the vertical face of one wedge and the slanted face of the other. The momentum imparted in the direction of rotation by a photon bouncing off the vertical face is greater than that imparted by bouncing off the slanted face. As a result, there is a net torque, speeding up the object's rotation (7, 8). In addition, infrared radiation emitted by the faces also produces a torque, and infrared YORP probably dominates on small solar system bodies, which tend to be dark. To test this notion, Paddack actually used light (which simulated the Sun) to speed up objects that were magnetically suspended in a vacuum.

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3.

Science 13 April 2007: Vol. 316. no. 5822, pp. 188 - 190 DOI: 10.1126/science.316.5822.188

Climate Change: Global Warming Is Changing the World

Richard A. Kerr

An international climate assessment finds for the first time that humans are altering their world and the life in it by altering climate; looking ahead, global warming's impacts will only worsen In early February, the United Nations--sponsored Intergovernmental Panel on Climate Change (IPCC) declared in no uncertain terms that the world is warming and that humans are mostly to blame. Last week, another IPCC working group reported for the first time that humans--through the greenhouse gases we spew into the atmosphere and the resulting climate change--are behind many of the physical and biological changes that media accounts have already associated with global warming. Receding glaciers, early-blooming trees, bleached corals, acidifying oceans, killer heat waves, and butterflies retreating up mountainsides are likely all ultimately responses to the atmosphere's growing burden of greenhouse gases. "Climate change is being felt where people live and by many species," says geoscientist Michael Oppenheimer of Princeton University, a lead author of the report. "Some changes are making life harder to cope with for people and other species."

The latest IPCC report (www.ipcc.ch/SPM6avr07.pdf) sees a bleak future if we humans persist in our ways. The climate impacts, mostly negative, would fall hardest on the poor, developing countries, and flora and fauna--that is, on those least capable of adapting to change. Even the modest climate changes expected in the next few decades will begin to decrease crop productivity at low latitudes, where drying will be concentrated. At the same time, disease and death from heat waves, floods, and drought would increase. Toward midcentury, up to 30% of species would be at increasing risk of extinction.

The working group's report had a difficult coming-out party on 6 April. Like the reports from the two other IPCC working groups (WGI--see Science, 9 February, p. 754--and WGIII, due out on 4 May), Working Group II's involved a couple of hundred scientist authors from all six continents analyzing and synthesizing the literature over several years. Reviews by hundreds of experts and governments generated thousands of comments. Twenty chapters totaling 700 printed pages led to a Technical Summary of 80 to 100 pages and a Summary for Policymakers (SPM) of 23 pages. Then came the hard part: the 4-day plenary session in Brussels, which brought together scientists and representatives of 120 governments. There, unanimity among governments is required on every word in the SPM, ostensibly to ensure that the phrasing clearly and faithfully reflects the reviewed science of the chapters.

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4.

Nature 446, 745-747 (12 April 2007) | doi:10.1038/446745a; Published online 11 April 2007

Cell Biology: Autophagy and Cancer

Beth Levine

Autophagy is the degradation of redundant or faulty cell components. It occurs as part of a cell's everyday activities and as a response to stressful stimuli, such as starvation. Connections with cellular life-and-death decisions and with cancer are now emerging.

How is autophagy induced?

Autophagy occurs when cells need to 'self-cannibalize' or degrade their constituents. Underlying 'housekeeping' levels of autophagy probably occur in most normal cells to prevent the accumulation of protein aggregates and defective cellular substructures. Certain environmental cues (such as starvation, high temperature, low oxygen, hormonal stimulation) or intracellular stress (damaged organelles, accumulation of mutant proteins, microbial invasion) activate signalling pathways that increase autophagy. Classically, most research on how autophagy is induced has focused on an enzyme called TOR kinase. This enzyme is a sensor of nutrient status and a master regulator of cell growth; it negatively regulates autophagy through its effects on a set of proteins known as autophagy-execution proteins. However, it is now clear that numerous signalling pathways, such as those involved in the control of cell growth, DNA-damage repair, a form of programmed cell death called apoptosis, and immunity, can also induce autophagy. It is still a mystery how these specific signals turn on the autophagic machinery.

What happens once autophagy is induced?

Once the cell receives the appropriate signal, the autophagy-execution proteins trigger a cascade of reactions that result in membrane rearrangements to form a double-membrane-bound vesicle called an autophagosome (Fig. 1). Initially, an 'isolation membrane' forms, although its origin is still controversial. The membrane surrounds the cytoplasmic contents to be degraded, and its edges fuse to form the autophagosome. This vesicle then fuses with a lysosome (or a vacuole in yeast), with the release of lysosomal digestive enzymes into the lumen of the resulting autolysosome. The sequestered cytoplasmic contents are degraded inside the autolysosome into free nucleotides, amino acids and fatty acids, which are reused by the cell to maintain macromolecular synthesis and to fuel energy production. The nutrient recycling and housekeeping functions of autophagy promote cell survival, although in certain contexts autophagy may also promote cell death (Fig. 2, overleaf).

Does autophagy also stop protein synthesis?

No. On the contrary, one of its evolutionarily conserved functions, through protein recycling, is to help maintain the synthesis of essential proteins when external nutrients are limited. Although certain stress stimuli that induce autophagy, such as starvation, turn off general protein synthesis, they also turn on the synthesis of specific stress-response proteins, including autophagy-execution proteins. So in this setting, the cell uses a coordinated strategy. To ensure that it has enough amino acids to synthesize the proteins that are essential for its survival, general protein translation is shut down and autophagy is activated.

What are autophagy-specific genes?

These are genes that are required for the execution of the autophagy pathway. Several of them encode proteins that are components of kinase complexes, which regulate the activity of proteins and lipids through the addition of a phosphate group. Alternatively, they encode components of protein-conjugation systems, which attach to each other or to membrane lipids to form the membrane of the autophagosome. Deletion of an autophagy-specific gene blocks autophagy in a cell or organism. These genes were first identified through genetic screens in yeast that included a search for genes that are essential for survival during starvation. Many of these yeast genes are also present in higher organisms, as are the underlying molecular mechanisms of autophagy. Although there seems to be a universal requirement in autophagy for 'autophagy-specific' genes, this does not mean that these genes are not involved in other cellular processes.

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5.

Nature 446, 744 (12 April 2007) | doi:10.1038/446744a; Published online 11 April 2007

Obituary: Knut Schmidt-Nielsen (1915–2007)

R. McNeill Alexander

Knut Schmidt-Nielsen, one of the all-time greats of animal physiology, died on 25 January. His influence on the subject was profound, not only through his original research but also through his books and the meetings he organized.

Schmidt-Nielsen was born in Norway but moved to the United States in 1946. Much of his finest work concerns life in deserts, where the combination of heat and drought makes survival particularly difficult. The most effective means of keeping cool depend on evaporation of precious water, either in the breath or as sweat, but kangaroo rats survive in the Arizona Desert with nothing at all to drink. They keep reasonably cool by spending the day in burrows and emerging only at night. But even at night they would lose much too much water in their breath if it were not for their remarkable noses. The air they breathe in is relatively cool and dry, but it is inevitably warmed in the body and becomes saturated with water vapour. To minimize water loss, this air must be cooled before it leaves the body to condense out most of the vapour.

With his first wife Bodil, Schmidt-Nielsen showed that the incoming air cools the surfaces of the nasal cavity, which, in turn, cool the air when it is breathed out again. He showed that the same principle operates in other mammals and birds, but is particularly effective in kangaroo rats because their nasal surfaces are enlarged by elaborate nasal bones known as turbinals. They also save water by producing exceptionally concentrated urine.

The countercurrent effect in the nose is vital to desert rodents. But it is potentially troublesome to dogs overheated by exercise, as they need to let water evaporate to cool themselves. With colleagues, Schmidt-Nielsen showed that panting dogs avoid the effect by breathing in through the nose but out through the mouth.

Unlike kangaroo rats, camels are too big to retire to burrows in the heat of the day. Working in the Sahara Desert, the Schmidt-Nielsens showed that camels avoid the water loss that evaporative cooling would incur by allowing their bodies to heat up by day and cool by night. A camel may start the morning with a body temperature of only 34 °C, but warms to 41 °C during the afternoon. This strategy would be ineffective for small animals such as kangaroo rats, because they would quickly heat up to lethal temperatures, but it works well for camels. Later, in Australia, Schmidt-Nielsen showed that camels' noses conserve water even more effectively than do those of kangaroo rats; hygroscopic surfaces dry the outgoing air.

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6.

Nature 446, 736-737 (12 April 2007) | doi:10.1038/446736a; Published online 11 April 2007

Solid-State Chemistry: Crystal tennis rackets

J. Michael McBride

The idea of bendy crystals, especially ones that move rapidly and reversibly in response to light, seems strange. Such materials have now been prepared — but how do they change shape so dramatically without cracking?

Most chemical reactions are accompanied by a change of molecular shape. Impressively, evolution has harnessed this effect to generate mechanical power for biological 'devices', for example, in muscles, where the bending of myosin upon release of adenosine diphosphate is used to drive one fibre past another1. In stark contrast, science has produced very few artificial analogues. In most cases, chemical transformations contribute to man-made mechanical devices only at the crudest level, by supplying a source of heat, or electrical energy, or indiscriminant swelling. Current work on nanodevices is changing this situation at the molecular level2, but problems in linking such devices together to achieve larger-scale motion have inhibited progress. On page 778 of this issue, Irie and colleagues3 describe a breakthrough in this area — a light-induced chemical transformation that bends crystals without shattering them.

So how does one go about exploiting molecular shape-changing to generate movement at the bulk level? For practical applications, the chemical transformation should be reversible — both chemically and mechanically — and the interconverting molecular states should generally be stable. Numerous reversible, light-induced reactions might fit the bill, possibly providing the basis for actuator devices that convert light into motion. For example, molecules can be constructed that have rigid double bonds at their centres. But when these compounds are irradiated with ultraviolet or visible light, rotation about the double bond becomes possible, and the molecules can change shape. Similarly, certain chains of six carbon atoms can form a ring upon irradiation, so as to flatten a previously bulky molecule. This process can sometimes be reversed by changing the wavelength of the irradiating light, and it is this sort of system that is used by Irie and colleagues3.

But for practical purposes, there is another requirement: the molecules concerned must be ordered and coupled so that millions or billions of them cooperate to achieve large-scale mechanical motion. This constitutes a greater challenge, especially when reversibility is important. A crystalline sample provides excellent order, but if the coupling between neighbouring molecules is too inflexible then the crystal will crack irreversibly as individual molecules change shape. An amorphous sample is less prone to cracking, but the reduced order makes it more difficult to optimize the arrangement of molecules so that their shape changes are macroscopically cooperative. Nevertheless, several tricks have been identified that impose suitable molecular orientation in amorphous films and liquid-crystalline films to achieve slow macroscopic bending or contraction upon illumination4.

So, a long-cherished aim of solid-state organic chemistry remains: to discover new single-crystal to single-crystal transformations, with a smooth transition between the crystal lattices of the starting material and the product. For this to happen, the product molecules must form randomly throughout the starting material, rather than establishing larger 'islands' of a separate crystal phase that would greatly disrupt the original bulk lattice. Such phase separation makes cracking all but inevitable, because just a 1% change in lattice spacing, caused by product formation, would force neighbouring lattices within a distance of 50 molecules to fall completely out of register.

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