This Week in Science

Science  27 Mar 2009:
Vol. 323, Issue 5922, pp. 1644
  1. Dissecting Drug Expulsion Portal


    P-glycoprotein (P-gp) is a transmembrane transporter protein with broad specificity for hydrophobic drugs found at the surface of many mammalian cells. P-gp detoxifies cells and, because of its ability to pump drugs out of the cell, has been implicated in multidrug resistance in cancer treatment. Aller et al. (p. 1718; see the Perspective by Sheps) now report crystal structures of mouse Pgp with and without cyclic peptide inhibitors bound in a large internal cavity. The inward-facing structures have two portals that allow entry of hydrophobic molecules directly from the inner leaflet of the lipid bilayer. Understanding in molecular detail how P-gp promotes cancer drug efflux will be key to preventing and reversing multidrug resistance in the future.

  2. Graphene at the Edge


    Although graphene is thought of as a uniform, two-dimensional material, the properties of a graphene specimen will depend on the structures and defects at its edges. Jia et al. (p. 1701) use Joule (resistive) heating to heal defects through the vaporization of carbon atoms. Tracking the process using electron microscopy revealed the main mechanisms by which sharp edges and step-edge arrays are stabilized into armchair and zigzag configurations. Girit et al. (p. 1705; see the cover) present a high-resolution transmission electron microscopy study of the structure and dynamics of graphene at the edge of a hole in a suspended, single atomic layer of graphene. The injection of electrons causes ejection of carbon atoms, leading to rearrangement of the bonds at the edges into a zigzag configuration, which represents the most stable form.

  3. Folding Forum

    The endoplasmic reticulum (ER) establishes and maintains a specialized environment capable of supporting the folding of secreted proteins. Reductionist approaches have focused on understanding the mechanism and biological role of a specific chaperone or degradation system in isolation. Jonikas et al. (p. 1693) present a complementary strategy using the cell's endogenous sensor of misfolding in the ER (the Ire1/Hac1 system) as a reporter to identify all the genes that contribute to ER folding. A remarkable array of different factors and processes were seen to contribute to ER folding. Measuring induction of the unfolded-protein response pathway in double mutants allowed the equivalent of hundreds of secondary screens in parallel and the systematic functional dissection of previously characterized and uncharacterized processes needed for proper ER function.

  4. Very Extreme Light Source

    The collapse of very massive stars can produce violent explosions accompanied by strong bursts of gamma-ray light. Typical gamma-ray bursts emit photons with energies between 10 kiloelectron volts (keV) and about 1 megaelectron volt (MeV). Rarely, photons with energies above 100 MeV have been observed, but the distances to their sources have been unclear. Now, Abdo et al. (p. 1688, published online 19 February) report that the Fermi Gamma-ray Space Telescope has detected photons with energies between 8 keV and 13 GeV, arriving from the gamma-ray burst 080916C, whose distance is known. These broad energy data, together with the distance to the burst, provide important constraints on the poorly understood gamma-ray burst emission mechanism.

  5. Fighting Friction

    If you rub two metal blocks against each other they will slide with a certain amount of resistance. If you push them together at the same time, the sliding motion will slow down and then suddenly cease due to a sudden jump in the friction between the two surfaces. To reduce friction, lubricants like oil are added. The coefficient of friction (COF) reflects this resistance to motion, and examples of materials with low COF can be found in the human body, such as in knee and hip joints, even at elevated pressures. While low friction synthetic materials have been fabricated, the low COF values are not retained at elevated pressures. Chen et al. (p. 1698) constructed phosphorylcholine group-containing polymeric brushes that showed extremely low COF values, even at high pressures. The polymer brushes retain a very large hydration shell, which enables easy sliding between two brush surfaces.

  6. A Wider Warmth

    The early Pliocene epoch from 5.3 to about 3 million years ago was much warmer than today. Despite this difference, the early Pliocene climate was very much like the preindustrial present in many important ways—including the amount of solar radiation Earth received, the concentration of atmospheric CO2, and a nearly identical geographic environment. However, there was no permanent ice sheet in the Northern Hemisphere, and global sea level was 25 meters higher. Why then was the world so different? Brierly et al. (p. 1714, published online 26 February) analyze new and published data about sea surface temperatures 4 million years ago that show that the meridional temperature gradient between the equator and the subtropics was much shallower than it is today, implying that the ocean tropical warm pool was much larger. An atmospheric general circulation model shows what major atmospheric circulation changes such a sea surface temperature field implies, with relevance for how climate warming may affect the future.

  7. A Stealthy Exit

    The mycobacterial pathogens that cause tuberculosis are difficult to work with because they grow very slowly, can require special laboratory containment facilities, and frequently cannot be grown independently of a host cell. Consequently, Hagedorn et al. (p. 1729; see the Perspective by Carlsson and Brown) have adopted a convenient model organism, the social amoeba Dictyostelium discoideum, which can be infected by certain mycobacteria and offers an analog for vertebrate macrophages—the preferred niche for tubercular mycobacteria. During their escape from Dictyostelium cells, mycobacteria use a so-called ejectosome. The ejectosome consists of a dense ring of actin surrounding a mycobacterium that is rupturing through the plasma membrane. The ejectosome is generated by mycobacteria that have escaped from phagosomes into the cytoplasm and requires the mycobacterial virulence locus RD1. The same type of structure could provide a route for mycobacterial spread between densely aggregated cells found in tubercular granulomatous disease.

  8. Of Twins and Brains

    Until now, brain imaging studies in twins have used an approach that is well suited for group studies, which minimize individual differences in the brain imaging response. However, genetic imaging studies are concerned with the detection of individual differences that require preprocessing and brain alignment techniques. Now Koten et al. (p. 1737) have examined differences in the patterns of brain activity among identical and fraternal twins during the performance of arithmetic verification and working-memory tasks. A multivariate pattern analysis allowed the identification of regions of activity that were activated either consistently or inconsistently across subjects, which could then be assessed for the effects of heritability. Genetic effects were mainly found in brain regions that were not consistently activated in all individuals, particularly during more complex or demanding tasks. Thus, individual differences in patterns of brain activity may result from genetic factors.

  9. Not Too Cold

    Ambient temperature affects the physiology, behavior, and evolution of organisms. Genetic variants that confer heat- or cold-resistance on organisms can be selected during a period of extreme climate change, later allowing populations to spread to geographic regions beyond the boundaries of the ancestral population. Takeuchi et al. (p. 1740), in a screen for flies with abnormal temperature preferences, isolated the gene encoding the Drosophila ortholog of dystroglycan (DmDG) (a glycosylated peripheral membrane, abnormalities of which can cause muscular dystrophy). When given a choice of moving within a gradient of temperatures, the mutant flies lacking DmDG preferred a temperature a few degrees cooler than did wild-type flies. This behavior was associated with an increased rate of mitochondrial oxidative metabolism in the animals, and flies engineered with a second mutation that caused decreased activity of the mitochondrial enzyme pyruvate dehydrogenase reversed the effect of loss of DmDG. The dystroglycan mutant flies were also resistant to cold, with about half of the flies able to survive near-freezing temperatures that killed almost all of the wild-type flies.

  10. Real-Time Visualization of HIV Entry

    The ability to visualize fluorescently labeled viruses in real time as they infect target cells will generate new understanding and potentially suggest novel targets for disease intervention. During infection, human immunodeficiency virus (HIV) is able to spread between immune cells without seeming to be exposed to neutralizing immune responses. Hübner et al. (p. 1743) captured high-resolution images of the formation of infectious structures called virological synapses during HIV infection of T cells. Dynamic membrane trafficking and an endocytic pathway for HIV transfer between cells appeared to be triggered by cell-cell contact. Continuous long-duration imaging suggests that this pathway can promote infectious HIV spread between T cells.

  11. Taking para-Hydrogen out for Its Spins

    Although nuclear magnetic resonance is a commonly used technique, it is actually relatively insensitive—it detects a population difference in spin states that is often a tiny fraction of total sample, even in very high magnetic fields. For imaging applications, one strategy for boosting the signal is hyperpolarization, in which molecules or atoms that have high nuclear spin polarization are used directly, or transfer their polarization to another molecule—for example, by forming a covalent bond. Adams et al. (p. 1708) show that polarization can be transferred to molecules such as pyridine without direct hydrogenation; reversible association of both molecules on the same metal complex is sufficient.

  12. Storing Spin Population in Singlet States

    Magnetic resonance imaging of organic molecules, such as metabolites, can be achieved with hyperpolarization methods that increase the population difference of spin states, but lifetimes tend to be short, on the order of seconds. Warren et al. (p. 1711) explore an alternative strategy for magnetic resonance imaging of organic molecules in the singlet states between strongly coupled spins in molecules. Populations can be stored in these disconnected eigenstates if the strength of spin coupling is sufficiently strong and retrieved through a chemical reaction. For example, spin populations can be stored for minutes in 13C-labeled diacetyl and retrieved through a hydration reaction.

  13. Inflammation Protection

    The immune system protects against infection by pathogenic microorganisms, but it also recognizes when the body has been injured. Burns, radiation exposure, and bruises all involve the immune system when responding to damaged tissue. Which signaling pathways recognize tissue damage and keep the resulting inflammatory response from getting out of hand? Chen et al. (p. 1722, published online 5 March; see the Perspective by Bianchi and Manfredi) now identify CD24, a costimulatory molecule of the immune system, and the sialic-acid binding lectin, Siglec-10 (or its mouse homolog, Siglec-G), as co-receptors required for protection against the immune response induced by tissue damage, but not infection, in mice. Through association with and inhibition of the molecules that are released following tissue damage, CD24 and Siglec-G protected mice from an otherwise lethal inflammatory response.

  14. Imaging the Battlefield

    The events that ensue after a virus invades a mammal's body are poorly known, but the pace and volume of the early immune response determines whether the host recovers or is overwhelmed. Li et al. (p. 1726) now visualize, map, and quantify these first events in macaques infected with simian immunodeficiency virus and in mice infected with strains of lymphocytic choriomeningitis virus. Depending upon these early events, the consequences of infection could be predicted. Virus-specific CD8+ T cells were seen to colocalize with infected cells. When the amplification of the host immune response outstripped the proliferation rate of the virus, the spread of virus-infected cells was contained, the virus eliminated, and the animal cured.

  15. Showing Up Shoals

    Ocean Acoustic Waveguide Remote Sensing enables the detection and mapping of the formation of very large fish shoals. Makris et al. (p. 1734) use this technology to quantify group formation in herring over oceanic scales of tens of kilometers. Apparently, scattered fish shoals are actually an interconnected cluster. When population kernels reach a critical density of 0.18 fish/m2 early in the evening, there is a rapid aggregation emanating as horizontal waves from the initial kernels, leading to the formation of dense shoals (>5 fish/m2) over tens of kilometers within tens of minutes. The imaging technology allows the size, shape, and depth profile of the shoal to be monitored over periods of days, providing valuable data on the dynamics of shoal formation and synchronous spawning.

  16. Jumping into Cancer Genes

    Recent cancer genome sequencing studies have uncovered a daunting number of genetic mutations in human tumors. How can we ascertain which of these mutated genes actively drive tumorigenesis and which are innocent passengers? Starr et al. (p. 1747, published online 26 February) identified genes causing colorectal cancer in mice by studying animals that developed intestinal tumors after the Sleeping Beauty transposon (a piece of DNA that “jumps” into random genes and alters their function) was selectively activated in the gut epithelium. A total of 77 genes were found to harbor transposon insertions. Remarkably, nearly 80% of these cancer-causing genes in mice had previously been shown to exhibit altered expression or function in human colorectal tumors, suggesting that they are likely to drive tumorigenesis.

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