This Week in Science

Science  19 Feb 2016:
Vol. 351, Issue 6275, pp. 827
  1. Structural Biology

    CRISPR Cas9 molecular scissors

    1. Guy Riddihough

    Cas 9 (green) uses RNA (white) to unravel DNA (blue) cutting sites

    ILLUSTRATION: BANERJEE ET AL./JANET IWASA/UNIVERSITY OF UTAH

    The CRISPR-associated (Cas) protein Cas9 is a molecular scissor for cutting DNA. The first step in the cutting reaction is the RNA-guided unwinding of the DNA double helix. Jiang et al. determined the structures of Cas9 bound to DNA unwound by the targeting RNA (see the Perspective by Chen and Bailey). Cas9 bends the DNA to allow guide RNA infiltration into the double helix. The two separated DNA strands, one bound to RNA, are subsequently positioned in the dual active sites of the protein for cutting.

    Science, this issue p. 867; see also p. 811

  2. Organic Chemistry

    A route to nitrile that bypasses cyanide

    1. Jake Yeston

    The toxicity of hydrogen cyanide (HCN) is well known. Nonetheless, numerous useful nitrile compounds contain CN groups, and the reaction of HCN with C=C double bonds is often used. Fang et al. now report an alternative to shuttle a CN group from one molecule to another that relies on Ni and Al catalysts (see the Perspective by Schmalz). This transfer procedure circumvents the need for HCN and can be applied to complex substrates using a simple sacrificial nitrile donor. It can also be run “in reverse” to derive an olefin of interest from a nitrile precursor.

    Science, this issue p. 832; see also p. 817

  3. Applied Physics

    Sensing single proteins with diamonds

    1. Ian S. Osborne

    Nuclear magnetic resonance is a powerful technique for medical imaging and the structural analysis of materials, but is usually associated with large-volume samples. Lovchinsky et al. exploited the magnetic properties of a single spin associated with a defect in diamond and manipulated it with a quantum-logic protocol. They demonstrated the magnetic resonance detection and spectroscopy of multiple nuclear species within individual ubiquitin proteins attached to a specially treated diamond surface at room temperature.

    Science, this issue p. 836

  4. Nanomaterials

    Dynamic DNA clustering of nanoparticles

    1. Marc S. Lavine

    The size and shape of nanoparticles can increase the cellular uptake and delivery of contrast agents and therapeutics. Ohta et al. created gold nanoparticles partly covered with DNA chains and with folic acid as the targeting molecule (see the Perspective by Parak). The particles could link together to hide the folic acid or to expose it on the surface, depending on the hybridization and overall particle configuration. The addition of complementary DNA allowed switching between structures, thus changing the way the particles interacted with cells.

    Science, this issue p. 841; see also p. 814

  5. Mucosal Immunology

    Keeping immune cells quiet on a diet

    1. Kristen L. Mueller

    Over thousands of years, our immune systems has evolved to distinguish self from foreign, perpetrating attacks on microbes but not ourselves. Given this, why do we fail to mount an immune response against most of the food we eat? Kim et al. compared normal mice, mice lacking microbes, and mice lacking microbes that were fed an elemental diet devoid of dietary antigens (see the Perspective by Kuhn and Weiner). Dietary antigens normally induced a population of suppressive immune cells called regulatory T cells in the small intestine. The cells were distinct from regulatory T cells induced by microbial antigens and prevented strong reactions against food.

    Science, this issue p. 858; see also p. 810

  6. DNA Repair

    A key player in cancer prevention

    1. Guy Riddihough

    Obstacles that block DNA replication can lead to chromosomal abnormalities and ultimately cancer. Fanconi anemia, for example, is caused by defects in the repair of DNA interstrand cross-links. The Fan1 nuclease was originally identified as a protein essential for this cross-link repair. Lachaud et al. now show that it does much more. It is recruited to stalled replication forks by ubiquitinated Fancd2 enabling the processing of these structures, thereby preventing chromosomal abnormalities and acting more broadly in cancer prevention.

    Science, this issue p. 846

  7. Neuroscience

    Glial cell properties dictated by neurons

    1. L. Bryan Ray

    Specialized astrocytes (green) are intimately associated with Purkinje neurons (magenta).

    PHOTO: TODD FARMER/MCGILL UNIVERSITY HEALTH CENTRE

    Neurons in the brain coexist with astrocytes, a type of glial cell, which help support many functions of their neighboring nerve cells. Farmer et al. now show that the support goes both ways (see the Perspective by Stevens and Muthukumar). They explored the influence of neurons on two specialized types of astrocytes in the mouse cerebellar cortex. The neurons produced the morphogen known as Sonic Hedgehog. Hedgehog signaling adjusted distinctive gene expression within the two astrocyte cell types. Thus, mature neurons appear to promote and maintain specific properties of associated astrocytes.

    Science, this issue p. 849; see also p. 813

  8. Seismology

    Crowdsourcing earthquake early warnings

    1. Kip Hodges

    The rapid distribution of earthquake warnings can reduce resulting loss of life and injury. Most earthquake early warning systems are based on data from specially designed seismic and geodetic networks. Kong et al. developed a system that gathers and distributes earthquake data from smartphone sensors, substantially improving our ability to provide near-real time warnings in areas where more traditional networks are unavailable.

    Sci. Adv. 10.1126.sciadv.01055 (2016).

  9. Cancer

    Killing cancer with a soft touch

    1. Yevgeniya Nusinovich

    Bleomycin is an effective chemotherapy drug that is used against multiple types of cancer. Unfortunately, it often causes lung fibrosis (or stiffening of the lungs), the severity of which correlates with the extent of exposure to the drug. To overcome this problem, Burgy et al. produced deglyco-bleomycin. This modified version of the drug was just as effective against several different models of cancer but did not cause any detectable fibrosis in mouse lungs. If these findings are confirmed in clinical testing, deglyco-bleomycin could be a valuable addition to the therapeutic regimens for treating a variety of human cancers.

    Sci. Transl. Med. 8, 326ra20 (2016).

  10. Microbiome

    Microbiota and infant development

    1. Caroline Ash

    Malnutrition in children is a persistent challenge that is not always remedied by improvements in nutrition. This is because a characteristic community of gut microbes seems to mediate some of the pathology. Human gut microbes can be transplanted effectively into germ-free mice to recapitulate their associated phenotypes. Using this model, Blanton et al. found that the microbiota of healthy children relieved the harmful effects on growth caused by the microbiota of malnourished children. In infant mammals, chronic undernutrition results in growth hormone resistance and stunting. In mice, Schwarzer et al. showed that strains of Lactobacillus plantarum in the gut microbiota sustained growth hormone activity via signaling pathways in the liver, thus overcoming growth hormone resistance. Together these studies reveal that specific beneficial microbes could potentially be exploited to resolve undernutrition syndromes.

    Science, this issue p. 10.1126/science.aad3311, p. 854

  11. Proteasome

    The yin and yang of proteasomal regulation

    1. Stella M. Hurtley

    The ubiquitin-proteasome pathway regulates myriad proteins through their selective proteolysis. The small protein ubiquitin is attached, typically in many copies, to the target protein, which is then recognized and broken down by the proteasome. Shi et al. found a repeat structure in the proteasome for recognizing ubiquitin as well as ubiquitin-like (UBL) proteins. Tandem binding sites allow the proteasome to dock multiple proteins. One of the bound UBL proteins is an enzyme that cleaves ubiquitin-protein conjugates, which antagonizes degradation. Thus, the repetition of related binding sites with distinct specificity achieves a balance of positive and negative regulation of the proteasome.

    Science, this issue p. 10.1126/science.aad9421

  12. Structural Biology

    AAA ATPase conformational high jinks

    1. Valda Vinson

    The protein p97 is an AAA adenosine triphosphatase (ATPase) that uses energy from ATP hydrolysis to regulate substrates involved in intracellular protein quality control. Its role in this central process makes it a target for cancer chemotherapy. Banerjee et al. used cryo-electron microscopy to determine high-resolution structures for multiple conformational states of this dynamic macromolecular machine. They also determined the structure of the ADP-bound state bound to an inhibitor. The structures give insight into nucleotide-driven structural changes that drive function and show how inhibitor binding prevents these conformational changes

    Science, this issue p. 871

  13. Structural Biology

    Insight into a bacterial membrane protease

    1. Valda Vinson

    Lipoproteins have key functions in many bacteria. They are synthesized in a precursor form that requires processing by enzymes that are essential in many pathogenic bacteria but have no equivalent in humans, making them potential drug targets. LspA is a key membrane protein involved in lipoprotein maturation in the bacterium Pseudomonas aeruginosa. Vogeley et al. determined the crystal structure of LspA bound to the antibiotic globomycin. Their structure and mutagenesis studies reveal how LspA processes substrate lipoproteins and indicate that globomycin inhibits the enzyme by binding to the active site. These findings should be useful in the development of new antibiotics.

    Science, this issue p. 876

  14. Ion Channels

    Calcium channels deliver a one-two punch

    1. Stella M. Hurtley

    To help generate long-lasting neuronal plasticity, CaV1.2 (L-type) calcium channels link electrical activity to nuclear gene expression. However, exactly how this coupling works is not fully understood. Li et al. developed a strategy to control two voltage-dependent signals—Ca2+ influx and nonionic conformational changes—separately. The combinatorial delivery of both signals was required to maximize transcription. Ca2+ influx first mobilized the kinase CaMKII from the cytosol. This allowed subsequent voltage-dependent conformational changes to localize the kinase at CaV1.2 signaling hot spots. Abnormality of nonionic conformational signaling is associated with neurological dysfunction in Timothy syndrome, a highly penetrant form of autism-spectrum disorder.

    Science, this issue p. 863

  15. Infectious Diseases

    Preparing for the next epidemic

    1. Julia Fahrenkamp-Uppenbrink

    As West Africa emerges from the Ebola epidemic that caused over 11,000 deaths, the next epidemic is emerging in Central and South America, where the rapid spread of Zika virus infections is implicated in clusters of birth defects. In a Perspective, Currie et al. discuss the lessons that can be drawn from the regional and international response to the Ebola epidemic. Their recommendations include strengthened national health services, multidisciplinary research that includes social and behavioral sciences, and a better-coordinated international response under the auspices of a well-funded and supported World Health Organization.

    Science, this issue p. 815

  16. Immunometabolism

    Unleashing natural killer cells

    1. John F. Foley

    The cytokine TGF-β can resolve inflammation and prevent autoimmunity, but it can also inhibit anti-tumor immune responses. Viel et al. found that TGF-β signaling suppressed the activity of a metabolism-regulating kinase in mouse and human natural killer (NK) cells, rendering them less cytotoxic towards tumor cells. NK cells deficient in a TGF-β receptor subunit decreased metastasis in mice, suggesting that enhancing metabolism in NK cells may provide a therapeutic strategy to kill cancer cells.

    Sci. Signal. 9, ra19 (2016).