Editors' Choice

Science  07 Jul 2006:
Vol. 313, Issue 5783, pp. 19

    Dating in Deep Water

    In modern times, deep ocean circulation has been governed by roughly equal fluxes of deep water formed in the North Atlantic and in the Southern Ocean around Antarctica. However, in the warmer climate of the early Cenozoic era, ∼55 million years ago (Ma), the Southern Ocean was the principal deep-water source, and a very different mode of global heat transport would have been operative. Thus, the precise timing of the transition from unipolar to bipolar deep-water circulation is of interest in climate as well as ocean studies.

    Via and Thomas have analyzed neodymium isotopic abundance data acquired from Southern Hemisphere sites that they chose to discriminate clearly between the two circulation patterns. They find that deep-water production in the North Atlantic began ∼33 Ma, as indicated by the divergence of isotope records from the more southerly Maud Rise and the more northerly Walvis Ridge. Among other implications, this finding suggests that the Greenland-Iceland-Faeroes Ridge—the sill over which deep water from the North Atlantic must flow in order to reach the southern portion of the ocean—must have deepened at that time. The dating of this event should improve understanding of climate changes that occurred during this dynamic interval of global cooling and tectonic evolution of the Atlantic basin. — HJS

    Geology 34, 441 (2006).


    Push Me-Pull You

    Proteins destined for secretion or for the cell surface are synthesized and cotranslationally inserted at the endoplasmic reticulum (ER). After entering the ER, proteins are guided to fold properly by chaperones such as protein disulfide isomerase (PDI). Sometimes, however, misfolding occurs, and under these circumstances, an elaborate process of quality control is set into motion. Misfolded proteins are either retained in the ER or retrotranslocated back into the cytosol for degradation by the proteasome; in both cases they are prevented from transiting further through the secretory pathway. Forster et al. have looked at the passage from the ER into the cytosol of cholera toxin, which cleverly travels via the retrotranslocation machinery. PDI promoted cholera toxin retrotranslocation, but the PDI-like protein p72 promoted ER retention. These two proteins both altered the conformation of cholera toxin to achieve the respective outcomes. Furthermore, this pair played a similar push me-pull you game with misfolded endogenous ER proteins. — SMH

    J. Cell Biol. 173, 853 (2006).


    A Balancing Act

    The intention of the recent TeGenero monoclonal antibody trial was to test the down-modulation of the chronic T cell activation underlying many inflammatory disorders. Crucially, the trial was based on preclinical data showing that a superagonist for the T cell costimulatory molecule CD28 would preferentially tilt the immunological balance in favor of suppressive T cell responses. However, the devastating outcome of the trial was wholesale acute T cell activation, serving to underscore how widely the activity of such reagents can vary under different conditions. Similarly, the clinically approved monoclonal antibody OKT3 can block T cell activity in certain settings, although scope for its therapeutic application is constrained by long-term effects associated with T cell activation.

    By administering a CD3-specific antibody orally rather than systemically, Ochi et al. were able to inhibit the onset and to treat therapeutically experimental autoimmune encephalitis in mice. These effects corresponded with uptake of the antibody by gut-associated lymphoid tissue, leading to the activation of mucosal regulatory T cells, which expressed latency-associated peptide and inhibited the T cell-mediated pathology via the cytokine transforming growth factor-β. This mechanism is distinct from the recognized depletion of T cells observed with systemic intravenous administration of a CD3-specific antibody. Thus, the results further highlight the profound divergence between the immune environments of the periphery and the mucosa. — SJS

    Nature Med. 12, 627 (2006).


    DNA Unzipper Found

    One of the critical steps an organism must perform in order to duplicate its genome is to unzip the two base-paired strands of DNA so that DNA polymerase can read and copy the information. Minichromosome maintenance (Mcm) proteins 2–7 are thought to be involved in unwinding double helical DNA in eukaryotes, but this six-subunit complex does not display helicase activity in vitro. Other proteins—Cdc45 and the four-subunit GINS (Go, Ichi, Nii, and San) complex—have also been implicated, but the precise composition of the active assembly has remained elusive.

    Moyer et al. have purified factors that interact with the Drosophila Cdc45 protein and find that they include both the Mcm hexamer and the GINS tetramer. The 11-membered CMG (Cdc45/Mcm2-7/GINS) complex is highly stable and, satisfyingly, exhibits adenosine triphosphate-dependent DNA helicase activity, which is lost or reduced upon immunodepletion of any of its components. Whether the Mcm proteins, which have all the structural features of a bona fide helicase, provide the unzipping activity in the CMG complex is not yet known. Intriguingly, GINS, like Mcm2-7, forms a ring, and the two might stack on top of each other, with DNA passing through the center. — GR

    Proc. Natl. Acad. Sci. U.S.A. 103, 10236 (2006).


    The Errant Heart

    Atrial fibrillation (AF) is a common and life-threatening condition in which erratic electrical activation of muscle cells in the upper chambers of the heart causes inefficient pumping of blood. As a result, blood pools in the heart and can form clots, which in turn increases the risk of stroke. Although AF typically arises in the context of other heart conditions, some patients present with AF on its own, and these individuals may provide valuable insights into the genetic determinants of the disorder.

    Studying heart tissue from 15 patients who developed idiopathic AF at an early age (their hearts were otherwise normal), Gollob et al. found that four patients carried missense mutations in the gene encoding connexin 40. Connexins are protein components of gap junctions, channels that conduct current between neighboring cells. Notably, in three patients, the mutations were not present in the germ line but instead were confined to heart tissue. Such tissue-restricted somatic mutations are a common cause of cancer, but this genetic mechanism is almost unprecedented in other human diseases. — PAK

    N. Engl. J. Med. 354, 2677 (2006).


    Idling Away Losses

    The development of metamaterials, in which electromagnetic behavior can be tuned by design, has already yielded such interesting effects as negative refraction and superlensing (subwavelength focusing). Progress in the fabrication of subwavelength-featured structures has carried these effects from the microwave regime through the terahertz and into the infrared region. However, one severe problem in the materials has been high signal losses, particularly due to absorption. Among the ideas floated to counter these losses is incorporating a gain medium into the design, though a major drawback to this approach is that it would indiscriminately amplify noise in addition to the desired signal.

    Popov and Shalaev propose an alternative: moving into the nonlinear regime and using optical parametric amplification. Their calculations show that mixing the signal field with an optimally tuned auxiliary electromagnetic pump field should produce an idler field at the difference frequency; this idler would then induce amplification of the signal field through three-wave mixing with the pump, thus compensating for absorption losses precisely at the signal frequency. The challenge now will be to implement these theoretical ideas and thereby achieve the promising applications of the materials. — ISO

    Opt. Lett. 31, 2169 (2006).


    Prearranged Luminescence

    Conjugated organic polymers such as poly(p-phenylenevinylene) (PPV) have attracted interest for use in sensors, light-emitting diodes, and other electronic applications. One advantage of these materials is their facile processability; for example, films can be fabricated under mild conditions by spin-casting from solution.

    Satrijo et al. show that a judicious choice of solvent for the spin-casting process can influence the structural and electronic properties of the resultant films. They studied the absorption and luminescence spectra of films prepared from a PPV derivative modified with chiral alkyl-substituted hydroquinone side chains. Films cast from chloroform, in which the polymer was highly soluble, were disordered but adopted an M-configured helical arrangement on annealing, as revealed from the circular dichroism spectrum and detection of right circularly polarized luminescence. When 1,2-dichloroethane (DCE) was used as the solvent, unannealed films emitted left circularly polarized luminescence, indicative of a kinetically stable, oppositely configured P helical structure. Spectra of the DCE solution before spin-casting supported self-assembly of helical aggregates that conserved their configuration during casting. By adding acetonitrile to the original chloroform solutions, the authors could induce complementary solution-phase aggregation, leading to right circularly polarized luminescence on irradiation. — JSY

    J. Am. Chem. Soc. 128, 10.1021/ja063027c (2006).