Editors' Choice

Science  25 Jul 2008:
Vol. 321, Issue 5888, pp. 466

    Modeling Microbicides

    Phase III clinical trials are underway to test the efficacy of antiretroviral (ARV)-based microbicides in preventing HIV transmission. However, the risk that ARVs may be absorbed systemically and promote the evolution of drug-resistant viral strains if used by HIV-positive women remains poorly characterized.

    Wilson et al. have modeled the effects of ARV-based microbicides on disease dynamics, either as part of a clinical trial or as a widespread public health intervention, in order to compare drugs with a high versus low potential risk for generating resistance. They find that a clinical trial will be unable to distinguish between high- and low-risk microbicides if HIV-positive participants are excluded on the basis of monthly tests for seroconversion (as planned for the upcoming dapivirine trial), given that resistance is expected to take at least 6 months on average to develop. If a high-risk microbicide is used as a public health intervention, the model predicts that the ratio of the number of prevented infections to the number of acquired resistant cases (the benefit-to-cost ratio) may not be much greater than 1. The ratio will be worse for women than for men, given that new cases of resistance will emerge in women initially and that drug-resistant strains have lower transmission efficiency than wild-type HIV. These results highlight the importance of collecting additional data on the resistance risks of new ARV-based microbicides before they are approved for popular use. — NM*

    Proc. Natl. Acad. Sci. U.S.A. 105, 9835 (2008).

    • * Nilah Monnier is a summer intern in Science's editorial department.


    Blue, Yellow, and Gold

    Mechanochromic compounds, which undergo a change in color or luminescence when solid samples are crushed or ground, can serve as detectors of mechanical action, but examples of such compounds are rare. Ito et al. synthesized a compound in which two C6F5Au groups are linked by a para CN(C6H4)NC ligand, and found that its photoluminescence changes from blue to yellow after grinding. Like other such compounds, its original luminescent state is restored upon dissolution and recrystallization, and this process could be repeated for 20 cycles without any decrease in luminescence. Structural and spectroscopic studies indicate that the long-lived blue emission in the crystal is intramolecular in origin and phosphorescent (a localized intraligand π-π* transition), whereas the yellow emission appears to arise from an amorphous phase characterized by aurophilic interactions: intermolecular interactions between gold atoms. — PDS

    J. Am. Chem. Soc. 130, 10.1021/ja8019356 (2008).


    Curvy Carbohydrates

    The global abundance of carbohydrate-based biopolymers and the prevalence of them in our diets support within the human gut a fascinating microbial ecosystem. Its role, from our point of view, is to degrade dietary polysaccharides; the flux through these pathways contributes as much as 10% of our daily calorie intake. One of the inhabitants of the human intestine is Bacteroides, and its starch utilization system (Sus) contains a number of regulatory and metabolic genes.

    Koropatkin et al. have determined the structure of the outer membrane protein SusD on its own and with linear and cyclic oligosaccharides bound. They find that the side chains of aromatic residues of SusD align to offer a curved surface that complements the helical conformation of maltoheptaose as well as the curvatures of α- and β-cyclodextrins (composed of six and seven glucose units, respectively). The multivalent, low-affinity interaction may facilitate hydrolysis of longer polysaccharides by the neighboring amylase SusG or the loading of oligosaccharides into the outer membrane importer SusC. — GJC

    Structure 16, 1105 (2008).


    Unscintillating Conversation

    Air-to-air and air-to-ground communication are generally carried out with radiofrequency transmitters and receivers. By comparison, optical-based communication systems offer a number of advantages, including higher bandwidth and the capacity to communicate information at higher rates, bundled with low weight, compact size, low power requirements, and the added security of a direct line-of-sight communication channel. However, the air turbulence that makes stars twinkle or scintillate at a detector presents a substantial problem for airborne optical communication. Unchecked, such turbulence will introduce a large amount of error into a communication channel. As an alternative to the relatively large adaptive-optics approach that uses a reference beam to remove the twinkle from the stars with wavefront engineering, Louthain and Schmidt show that a multiple-transmitter approach using several optical beams can also work. Their numerical simulations take into account a number of factors such as beam separation, phase difference, and angle of propagation of the individual beams. By averaging out the contribution from turbulence-induced shifts they show that the multiple-beam approach can significantly reduce the bit-error rate in messages over the optical channel. — ISO

    Opt. Express 16, 10769 (2008).


    Moving Through a Crowd

    Amigrating eukaryotic cell has a dense mesh of cortical actin at its leading edge, with long parallel actin bundles extending into microspikes and filapodia. Myosin X localizes at the ends of filapodia, where it may be involved in processes such as adhesion and signaling. How does myosin X find the appropriate actin filaments and travel along them to reach its destination?

    Nagy et al. show that although myosin X processive runs on single filaments are short and rare, it moves robustly and at length on fascin-bundled actin, which makes up the core of filapodia. Myosin X has a short neck so that its step size is probably smaller than the actin pseudo-helical repeat, which might account for its low processivity on single filaments. On actin bundles it can move with one head tracking one filament and the other head on the adjacent filament. Furthermore, myosin X was observed to move even farther and faster on artificially bundled (by molecular crowding) actin, suggesting that filament proximity facilitates its movement rather than structural features specific to actin monofilaments. — VV

    Proc. Natl. Acad. Sci. U.S.A. 105, 9616 (2008).


    Editing T Cells

    The chemokine receptor CCR5 is one of the major docking sites that HIV uses to enter T cells, and individuals carrying a homozygous deletion mutation in CCR5 are resistant to HIV infection. Hence, interfering with the HIV-CCR5 interaction has become the goal of several small-molecule drug design projects.

    Perez et al. have instead taken the approach of disrupting CCR5 by introducing a double-stranded break into the gene itself. Zinc-finger nucleases were designed to bind to and cleave at specific sequences found only in CCR5; endogenous DNA repair pathways have the effect of introducing deletions or insertions that yield a truncated or nonfunctional protein. Cultured human T cells that were transduced with a vector expressing the zinc-finger nucleases were resistant to HIV infection, and long-term expansion of these cells in culture did not reduce their resistance. In a mouse model of acute HIV infection, animals treated with nuclease-modified human T cells had a lower plasma viral load than control mice, along with higher T cell counts, suggesting that genome editing might be used therapeutically to provide a pool of HIV-resistant T cells. — LC

    Nat. Biotechnol. 26, 808 (2008).


    Fast Rising Hormone

    Fibroblast growth factor 21 (FGF21) has recently taken center stage as a key metabolic hormone that helps the body to adapt to starvation. When mice are fasted, FGF21 expression levels in the liver rise dramatically. In turn, FGF21 stimulates the release of fatty acids from adipose tissue and promotes their conversion in the liver to ketone bodies, which can be used as an energy source when carbohydrates are scarce; FGF21 also promotes torpor, an energy-conserving state in mice characterized by a reduction in body temperature and physical activity.

    Inagaki et al. show that the role of FGF21 in programming energy conservation during starvation may be even broader. Through the use of transgenic mice, they found that FGF21 mimics the inhibitory effects of fasting on organismal growth at both the phenotypic and molecular levels. The transgenic mice were smaller than their wild-type counterparts despite equal or greater food intake. Although the transgenic mice had higher levels of circulating growth hormone (GH) than controls, they appeared to be resistant to its actions. In the liver, FGF21 reduced the expression of a major mediator of GH action—the transcriptional regulator STAT5—and decreased the expression of key target genes implicated in organismal growth, including the gene encoding insulin-like growth factor 1 (IGF-1). Whether FGF21 has similar effects in humans remains to be determined. — PAK

    Cell Metab. 8, 77 (2008).

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