This Week in Science

Science  28 May 2004:
Vol. 304, Issue 5675, pp. 1207
  1. Human Insulin Signaling


    The most common forms of Type 2 diabetes are thought to arise from the interaction of many different genes and life-style factors. As is true for other complex diseases, the genetic factors contributing to the pathogenesis of diabetes are more readily identified by studying rare, monogenic forms of the disease. George et al. (p. 1325) find that a family showing autosomal dominant inheritance of severe insulin resistance and diabetes carries a mutation in the serine-threonine kinase AKT2, which inactivates its function. Earlier studies of mice had identified AKT2 as a key player in the insulin signaling pathway, and the new genetic data underscore the protein's important role in human diabetes.

  2. An Excited Kondo System

    The tunability of mesoscopic devices allows their use as testbeds for studying many-body quantum-mechanical phenomena. One such phenomenon is the Kondo effect, in which an unpaired electron in a quantum dot can mimic magnetic behavior and interact with surrounding electrons. Measurements to date, however, have concentrated on systems under equilibrium conditions. Kogan et al. (p. 1293; see the Perspective by Wingreen) made conductance measurements on a single-electron transistor exposed to microwave excitation. The subsequent development of Kondo satellites confirms a long-standing theoretical prediction and also should allow many-body quantum-mechanical effects to be studied under nonequilibrium (i.e., operational) conditions.

  3. Microfluidic Reductions

    Although most applications of microfluidics in chemistry have focused on separations and analysis, the high contact areas and potential for rapid mixing suggest advantages for synthesis as well, especially for cases where multiple phases must come into contact. Kobayashi et al. (p. 1305) have developed a microfluidic reactor for catalytic hydrogenations in which the organic phase is in contact with supported palladium catalyst particles immobilized on the glass sidewalls. At sufficiently high flow rates, hydrogen flows through the center of the channels, which greatly enhances the reaction rates. The reduction of double bonds, as well as deprotection reactions, could be completed quantitatively in 2 minutes.

  4. Linking Molecular Rings


    In organic synthesis, closing a ring in a molecule is often challenging enough, but chemists can now manage the closure of one ring through an existing ring on another molecule. Two reports now take ring linking to extremes by exploiting supramolecular interactions to guide the assembly process (see the Perspective by Siegel). Chichak et al. (p. 1308) have formed a molecular Borromean ring, in which three rings are linked such that cutting one link also separates the other two. Wang et al. (p. 1312) link two molecules, each with four rings, through the other set of rings.

  5. Making Oneself Presentable

    Once activated, cytotoxic CD8+ T cells react to changes in the protein content of a cell that take place when the cell becomes virally infected or transformed. Degraded protein fragments, which are generated by the proteasome, associate with class I major histocompatibility proteins within the endoplasmic reticulum and traffic to the cell surface to be scanned by responsive T cells. However, in order to prime a naïve T cell, the first encounter with peptide must be accompanied by an array of activation signals, which are generally only provided by professional antigen-presenting cells (APCs). The APCs must somehow acquire peptides without themselves being infected or transformed (see the Perspective by Ploegh). Studies by Wolkers et al. (p. 1314) and Norbury et al. (p. 1318) show that this process, which is known as cross-priming, depends critically on the location of the peptide within its parent protein. Peptides derived from regions proximal to, or within, the signal sequence were profoundly inefficient at stimulating T cells, when compared with more distal peptides—presumably because signal sequences are degraded most quickly and are present at very low levels in the cell. A critical parameter in determining cross-presentation efficiency is the acquisition of intact proteins or peptides, rather than their proteasome-generated products, by the APC.

  6. Fluid Source for Seismic Slip

    The subduction of Philipine Sea plate beneath the Eurasian plate has created the Nankai Trough off the coast of Japan and also yielded several great earthquakes. The northernmost segment of the Nankai trough has not had an earthquake, but instead the two plates creep past one another in seismically-silent slip events. Kodaira et al. (p. 1295) have determined that the region is creeping because of a zone of high pore fluid pressure is trapped on the downgoing side of a subducted ridge.

  7. Reviewing Hormone Replacement Therapy

    Many women have received hormone replacement therapy to alleviate symptoms associated with menopause. As an added benefit, steroid hormones were thought to reduce the risk of coronary heart disease and prevent bone loss in women. A large-scale clinical trial, termed the Women's Health Initiative (WHI), aimed to determine the risks and benefits of hormone replacement therapy. Turgeon et al. (p. 1269) review the WHI data based on what is known about the molecular interactions and pharmacology of replacement hormones. The relative risks and benefits revealed by the WHI study should only be considered in the light of the experimental design used.

  8. Stress and Degeneration

    Mutations in the protein parkin, an E3 ubiquitin ligase, cause degeneration of nigrostriatal dopamine neurons and lead to a familial form of Parkinson's disease (PD). Chung et al. (p. 1328, published online 22 April 2004) show that parkin can be S-nitrosylated both in vitro and in vivo and that S-nitrosylation blocks its ubiquitin E3-ligase activity as well as its protective function. The finding that nitrosative stress can impair the function of parkin links a familial form of PD to the more common sporadic form of PD in which nitrosative and oxidative stress are thought to be important factors of pathogenesis.

  9. Regenerating Lost Germline Stem Cells

    The invertebrate germ line is an excellent model system to elucidate stem cell biology. Jak-STAT signaling maintains germline stem cell self-renewal in Drosophila testis. Brawley and Matunis (p. 1331, published online 13 May 2004) now find that removing and then restoring Jak-STAT signaling in this system results in the regeneration of lost germline stem cells. These stem cells arise from the dedifferentiation of clusters of interconnected spermatogonial cells. Thus, even after spermatogonia have initiated differentiation, under the right conditions they can revert to germline stem cells.

  10. Maintaining Neural Stemness


    The ability to expand neuronal stem cell cultures has been hampered by their tendency to “mature” in culture, reducing their ability to generate neurons rather than glial cells. Shen et al. (p. 1338, published online 1 April 2004; see the Perspective by Wurmser et al.) now show that endothelial cells, but not vascular smooth muscle cells, promote self-renewal and inhibit the differentiation of neural stem cells, which allows the generation of large flat sheets of stem cells. When the endothelial cells are removed, the sheets differentiate and retain their ability to make neurons, including projection neurons normally made in the early embryo, as well as glia. Growth with endothelial cells thus allows expansion of neural stem cells while maintaining multipotency.

  11. Bilateral Versus Radial Symmetry During Evolution

    It is thought that bilaterians, which display symmetry along an anterior-posterior axis and a dorsal-ventral axis, may have evolved from an organism similar to modern cnidarians, the latter of which includes sea anemones, corals, hydras, and jellyfish. Cnidarians are generally believed to be radially symmetrical animals, but some cnidarians, such as the sea anemone Nematostella, display bilateral symmetry with an oral-aboral axis and a directive axis, which is orthogonal to the oral-aboral axis. To determine whether bilateral symmetry in cnidarians and bilaterians are homologous or convergent, Finnerty et al. (p. 1335, published online 6 May 2004; see the Perspective by Holland) examined the expression patterns of genes involved in establishing the axes of the sea anemone. They conclude that bilateral symmetry evolved prior to the divergence of bilaterians and cnidarians.

  12. Reflecting on Earth's Climate

    Earth's albedo—the fraction of sunlight that is reflected back to space as shortwave radiation—is one of the parameters that control the temperature of the atmosphere. One way to estimate Earth's albedo is to analyze global cloud coverage and surface characteristics, such as vegetation cover and mineralogy, and attempt to calculate how much sunlight is reflected. However, this process is complex, and different attempts have produced different results. Another way is to measure “earthshine,” the amount of light reflected by Earth and re-reflected by the dark side of the moon. Pallé et al. (p. 1299) performed both analyses to cross-validate the techniques and to estimate Earth's albedo for periods when satellite analyses of cloud coverage are not available. They find that there was a steady decrease in Earth's reflectance from 1984 to 2000, followed by a complete reversal of the decline after 2000. The radiative forcing implied by these decadal changes may have had an impact on climate.

  13. Elastic Actin Networks

    The protein actin forms a key part of the cytoskeletal network in cells, which helps to organize and maintain the cell's shape. The mechanical properties of the protein, which can form cross-linked networks, is not known, but is of importance in understanding how cells respond to mechanical deformation. Most binding proteins also impart flexibility on the cross-linked network, which makes it hard to isolate the contribution of the actin. Gardel et al. (p. 1301) use scruin, an actin-binding protein that forms rigid, permanent bonds, to both cross-link and bundle the actin filaments and thus isolate and account for the mechanical properties of the actin network. They find remarkable changes to the rheological properties, with sudden orders-of-magnitude changes in the elastic modulus when the network forms at critical scruin concentrations.

  14. Plus Ça Change?

    Generally speaking, noncoding segments of genomes change more rapidly than coding regions. Bejerano et al. (p. 1321, published online 6 May 2004) now describe a class of short genetic elements (>200 base pairs) in the human genome that has been extraordinarily conserved for 300 to 400 million years. Orthologs showed 100% identity for human, mouse, and rat sequences; slightly lower identity in chicken and dog; and some similarity observable in fish. RNA binding genes and transcription regulators were frequently found near these ultraconserved elements. Although the function of these elements has not yet been determined (nor the mechanism that preserved them), a working hypothesis is that they were important in vertebrate evolution.