Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques Science (IF 37.205) Pub Date : 2017-09-20 Ling Xu, Amarendra Pegu, Ercole Rao, Nicole Doria-Rose, Jochen Beninga, Krisha McKee, Dana M. Lord, Ronnie R. Wei, Gejing Deng, Mark Louder, Stephen D. Schmidt, Zachary Mankoff, Lan Wu, Mangaiarkarasi Asokan, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Jochen Kruip, Rebecca Sendak, Young Do Kwon, Tongqing Zhou, Xuejun Chen, Robert T. Bailer, Keyun Wang, Misook Choe, Lawrence J. Tartaglia, Dan H. Barouch, Sijy O’Dell, John-Paul Todd, Dennis R. Burton, Mario Roederer, Mark Connors, Richard A. Koup, Peter D. Kwong, Zhi-yong Yang, John R. Mascola, Gary J. Nabel
The development of an effective AIDS vaccine has been challenging due to viral genetic diversity and the difficulty in generating broadly neutralizing antibodies (bnAbs). Here, we engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: 1) the CD4 binding site, 2) the membrane proximal external region (MPER) and 3) the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to human bnAbs, and conferred complete immunity against a mixture of SHIVs in non-human primates (NHP) in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and could be applicable for diverse diseases, including infections, cancer and autoimmunity.
Refilling the coral reef glass Science (IF 37.205) Pub Date : 2017-09-22 David Obura
Coral reefs around the world have suffered from 3 years of coral bleaching, following three decades of record high temperatures. It is now clear that coral reefs cannot survive, unchanged, under climate change. Their final state will depend not only on societal conviction to restore coral health but also on the ability to sustain investments and action that support this commitment.
News at a glance Science (IF 37.205) Pub Date : 2017-09-22 Catherine Matacic
In science news around the world, the U.S. federal government targets four national monuments for downsizing, Romania slashes its science budget, and a sexual harassment case roils the University of Rochester in New York. Also, the National Institute of Standards and Technology gets a new leader, and the former head of the Centers for Disease Control and Prevention launches a new initiative to save 100 million lives through better health. In the physical sciences, the biggest U.S. radio astronomy observatory launches a 7-year sky survey, and cats are—according to one of this year's Ig Nobel Prize winners—both a solid and a liquid. Plus, a sting on predatory journals willing to sell authorship and the long tale of the Christmas Island bat, now officially extinct.
A fiery finish to Cassini's long run at Saturn Science (IF 37.205) Pub Date : 2017-09-22 Paul Voosen
Last week, after 13 years of exploration, NASA's Cassini spacecraft plunged into the upper reaches of Saturn's atmosphere at 123,000 kilometers per hour and melted away. The spacecraft's demise, necessitated by dwindling fuel and a need to protect two of Saturn's 62 moons from potential microbial contamination from Earth, brought forth a global outpouring of sentiment. Although pathos ruled for a day, Cassini's scientists are eager to get back to work. The spacecraft has already revolutionized understanding of gas giants and, with its discoveries of hydrogen-rich water plumes on Enceladus and methane lakes on Titan, the potential for life to exist beyond the classic "habitable zone." But its final 22 orbits could reveal insights into Saturn's rings and murky interior.
A legacy of discovery Science (IF 37.205) Pub Date : 2017-09-22 Paul Voosen
Over 13 years and 293 orbits, Cassini produced more than 450,000 images. They exposed a Saturn system rich with mystery—and two potentially habitable moons. The insights began with the Huygens probe, dropped on Titan—Saturn's largest moon—revealing a world of hydrocarbons, and continued on to Enceladus, a tiny frozen moon, where Cassini spotted jets of water spewing from its south pole, signs of a liquid water ocean under a thin icy crust. The spacecraft and its international team watched storms on Saturn's placid surface and, as its long seasons turned to summer, spotted a mysterious hexagonal jet stream on its north pole.
Russia heightens defenses against climate change Science (IF 37.205) Pub Date : 2017-09-22 Angelina Davydova
Earlier this month, Russia's prosecutor's office demanded that the environment ministry take steps to increase the accuracy of weather forecasts in light of a changing climate. The new charge reflects a sea change in Russia's views about climate change and how the nation must respond. Until recently, tackling climate change was a low priority for the federal government. One reason is complacence, because Russia's greenhouse gas emissions have already plummeted since the collapse of the Soviet Union. Another is political: Russia's economy depends heavily on pumping oil and gas out of the ground. But in August, Moscow city released a draft climate change adaptation plan, and other regions are working on their own plans. Still, although Russia is bracing for climate change, it has shown little desire to rein in carbon emissions.
Why is the flu vaccine so mediocre? Science (IF 37.205) Pub Date : 2017-09-22 Jon Cohen
With flu season around the corner in the United States and Europe, the push has begun once again to encourage people to receive their annual shots. But over the past few years, it's become increasingly clear that the level of protection offered by the vaccine varies widely each flu season, from 10% to 60%. And new research has revealed surprising reasons for its lackluster performance. For decades, it appeared that the vaccine had an efficacy of 70% to 90%, but scientists now know that's because they were using a misleading test—replaced in the 1990s—to assess whether it protected people. The traditional explanation for failure also has been revamped. The flu strains selected for the vaccine change each year based on what's in circulation, and scientists long blamed failure on mutations that occur in the circulating viruses in the 6–8 months that pass between the vaccine being manufactured and used. But these "mismatches" sometimes occur in years when there's solid protection, and some years with lots of failure have good matches. It turns out that other forces at work include mutations in the strain selected for the vaccine during the manufacturing process, which grows the virus in eggs. People's prior exposure to influenza also can bias their immune system toward a response that undermines that vaccine-triggered immunity. And the vaccine strain selection process itself relies heavily on the ferret animal model, which can mislead, too. There's an increasing call now to improve the vaccine and organize the research community to more collaboratively try to develop a "universal" flu shot that works against many strains and lasts for many years, if not a lifetime.
Researchers parse ecosystems fueled by chemistry, not light Science (IF 37.205) Pub Date : 2017-09-22 Elizabeth Pennisi
When the first deep-sea vent creatures came into view 40 years ago through a porthole of the submersibleAlvin, everyone was speechless, as no one expected to find life thousands of meters deep. This luxuriant ecosystem clustered around volcanic vents did not draw sustenance from the sunlit world, like most living things. Instead, these creatures all hosted "chemosynthetic" bacteria, redefining the limits of the types of ways animals can make a living. Since then biologists have discovered nonphotosynthetic food webs not just at volcanic vents around the world, but also at cool seafloor oil seeps, on sunken logs and animal carcasses, and in seagrass beds and mudflats. And new technologies now are enabling researchers to unravel these intricate chemosynthetic food webs. They are discovering new sources of energy, new capabilities of these bacteria, and have a greater appreciation of the complex interconnections not just among organisms in these environments, but also with organisms in the great ocean and beyond.
How ApoE4 endangers brains Science (IF 37.205) Pub Date : 2017-09-22 Emily Underwood
Since 1993, when theapolipoprotein E4(ApoE4) genetic variant was found to multiply the risk of the most common form of Alzheimer's disease as much as fourfold, researchers have probed its connections to the protein fragment β-amyloid, the dominant suspect for the cause of the illness. This week, however, a new study showed thatApoE4's most toxic effects may result from a damaging immune response to a different protein, tau. The study shifts the terms of an old debate over whether Alzheimer's disease treatments should focus on tau or amyloid, by suggesting both could be targeted throughApoE4.
Death watch for climate probe Science (IF 37.205) Pub Date : 2017-09-22 Paul Voosen
The Gravity Recovery and Climate Experiment (GRACE), which has monitored minute shifts in Earth's gravity to reveal the unexpectedly rapid melt of polar ice sheets and the drawdown of underground aquifers, will soon make its final science run, NASA announced last week. After running a decade beyond its planned life, one of its tandem satellites is nearly out of fuel. In October, GRACE will begin its final measures before going dark a month later. Its delayed successor, the $550 million GRACE Follow-On, will launch no sooner than next year thanks to troubled launch plans, leaving a gap in climate records.
Embryo edit makes human ‘knockout’ Science (IF 37.205) Pub Date : 2017-09-22 Gretchen Vog
For the first time, scientists have used gene-editing techniques on human embryos to probe how they develop. The study is an important proof of principle; previous human embryo–editing research has focused instead on correcting faulty genes. The new experiments are also a first test of the United Kingdom's carefully crafted embryo-editing research regulations, which require that researchers undergo a review by a government authority and receive a license before moving forward. Kathy Niakan, a developmental biologist at the Francis Crick Institute in London, applied in 2015 to use the CRISPR editing technique on human embryos to learn more about the genes active in early development. The researchers planned to focus first on OCT4, known as a marker for pluripotent stem cells—cells that can become all tissues in the body. Niakan's group used CRISPR to "knock out," or deactivate, the gene that codes for OCT4 in 37 single-cell human embryos left over after in vitro fertilization treatments and donated by couples. In the human embryo knockouts, placental cells failed to form, indicating that OCT4 plays an earlier role in humans than it does in mouse embryos.
China's childhood experiment Science (IF 37.205) Pub Date : 2017-09-22 Dennis Normile
There is an enormous economic gap between China's booming coastal regions and its impoverished interior. And the disparity in economics is reflected in differing approaches to raising young children. The urban middle class embraces modern parenting with intense interaction between parents and children. Rural caregivers unknowingly fail to provide the intellectual and social stimulation that child development experts now believe is crucial for the healthy development of the whole child. The shortcomings are exacerbated when parents migrate away from the home for work, leaving children in the care of grandparents who have limited educations themselves and even less exposure to modern parenting. Hoping to rectify this imbalance, economist Scott Rozelle of Stanford University in Palo Alto, California, is heading an experimental intervention that coaches rural mothers and grandmothers in caring for young children, especially during the first 1000 days of a child's life. Early childhood development experts believe that effective parenting in the home for children younger than 3 years old sets the stage for later educational achievement and adult health.
Toward pesticidovigilance Science (IF 37.205) Pub Date : 2017-09-22 Alice M. Milner, Ian L. Boyd
Agricultural pesticides are an important component of intensive agriculture and, therefore, of global food production. In the European Union, ∼500 active substances used in pesticides are approved, including insecticides, fungicides, herbicides, and plant growth regulators. When used at industrial scales, pesticides can harm the environment (1), but there is a trade-off between this effect and the need to produce food. Recent uncertainties about the health and environmental effects of glyphosate herbicide and neonicotinoid insecticides underline the need for regulation to be sensitive to this trade-off (2,3). Better regulation is needed to control how pesticides are used and affect the environment at a landscape scale.
RNA localization feeds translation Science (IF 37.205) Pub Date : 2017-09-22 Imre Gáspár, Anne Ephrussi
The digestive tract has to cope with the challenge of functioning efficiently despite irregular cycles of eating and fasting. Digestion and absorption of nutrients require large quantities of proteins, mainly enzymes and transporters (1). Although these proteins must be available in the epithelial cells that line the stomach and intestines within minutes upon feeding, their continuous production would impose high upkeep costs on the fasting organism. On page 1299 of this issue, Mooret al.(2) identify a mechanism that may account for the responsiveness of the digestive system: The monolayer of enterocytes (which form the intestinal epithelium) controls protein expression at the level of translation, through regulated RNA localization.
The social origins of persistence Science (IF 37.205) Pub Date : 2017-09-22 Lucas P. Butler
Effort and hard work have long been regarded as key to achievement and success. But individuals hold different beliefs about how important effort is in determining success, relative to pure talent or natural skill. Recent research has shown that holding a growth mindset—that is, a set of beliefs that emphasize the malleability of intelligence and skill, focus on hard work and effort rather than talent, and view failures and setbacks as potential learning opportunities—may predict later academic and even life success (1–3). Moreover, teaching students to focus on effort and see failures as learning opportunities presents a promising lever for interventions to boost individual achievement and outcomes (4). But are such beliefs or mindsets something akin to a heritable personality trait, or could adults play a key role in fostering it in children from a very young age? On page 1290 of this issue, Leonardet al.(5) show that infants can learn the value of hard work simply by observing an adult try hard to achieve a goal, leading them to try harder when they face their own challenging task.
Advances in organ transplant from pigs Science (IF 37.205) Pub Date : 2017-09-22 Joachim Denner
Xenotransplantation, where tissue from one species is transplanted into a different species, is currently under development to help alleviate the increasing shortage of human tissues and organs for transplantation to treat organ failure. For several reasons, which include the size and physiology of the organs, the ease of genetic modification and cloning, and the large number of progeny and short reproduction cycle, pigs are the animals of choice for organ transplant in humans. Three major problems need to be solved before xenotransplantation becomes a clinical reality: immunological rejection, physiological incompatibility, and the risk of transmission of porcine microorganisms that are able to induce a disease (zoonosis) in the human recipient. On page 1303 of this issue, Niuet al.(1) demonstrate how to increase the safety of xenotransplantation.
Angular momentum can slow down photoemission Science (IF 37.205) Pub Date : 2017-09-22 Vladislav S. Yakovlev, Nicholas Karpowicz
Photoemission spectroscopy, where the absorption of an energetic photon by a material results in the emission of an electron, is an invaluable source of information about electronic structure. Electrons gain their kinetic energies by interacting with both light and their surroundings. In a solid, for example, this makes it possible to measure band energies, energies and lifetimes of quasiparticles, spectral density of states, surface states, and both elastic and inelastic scattering processes. Since the photoelectric effect was explained by Max Planck and Albert Einstein, the fundamental processes behind photoemission have been thoroughly studied in both experiment and theory, but do we fully understand the dynamics of electron emission? On page 1274 of this issue, Sieket al.(1) show that the angular momentum of the electron affects which electrons are emitted first from an atom in a solid.
New angle on cosmic rays Science (IF 37.205) Pub Date : 2017-09-22 John S. Gallagher, Francis Halzen
Cosmic rays are nuclei that have been accelerated to relativistic velocities by astrophysical sources, arriving at Earth after traversing the space between us and the source. As electrically charged particles, they are deflected by magnetic fields, which scramble their directions in space (1). Finding deviations from the highly isotropic angular distribution of high-energy cosmic rays in the sky has long been a prime goal of cosmic-ray researchers. Marginal detections have been reported in the past that failed to hold up. On page 1266 of this issue, The Pierre Auger Collaboration (2) report a strong detection of a pronounced anisotropy in the arrival directions of cosmic rays with energies (E) of ≥8 EeV (8 × 1018electron volts), indicating that they are of extragalactic origin.
Sociotechnical transitions for deep decarbonization Science (IF 37.205) Pub Date : 2017-09-22 Frank W. Geels, Benjamin K. Sovacool, Tim Schwanen, Steve Sorrell
Rapid and deep reductions in greenhouse gas emission are needed to avoid dangerous climate change. This will necessitate low-carbon transitions across electricity, transport, heat, industrial, forestry, and agricultural systems. But despite recent rapid growth in renewable electricity generation, the rate of progress toward this wider goal of deep decarbonization remains slow. Moreover, many policy-oriented energy and climate researchers and models remain wedded to disciplinary approaches that focus on a single piece of the low-carbon transition puzzle, yet avoid many crucial real-world elements for accelerated transitions (1). We present a “sociotechnical” framework to address the multidimensionality of the deep decarbonization challenge and show how coevolutionary interactions between technologies and societal groups can accelerate low-carbon transitions.
The legacy of the Spanish flu Science (IF 37.205) Pub Date : 2017-09-22 Suzanne Shablovsky
Between 1918 and 1920, the Spanish flu infected a third of the global population. It claimed more lives than either World War I or World War II. Nearly a century later, we are still struggling to understand the extent of this pandemic. It crops up from time to time in popular science and history, but no one has yet to take as wide-sweeping an approach as Laura Spinney does in her new book,Pale Rider.
Sleight of hand Science (IF 37.205) Pub Date : 2017-09-22 Daniel Casasanto
What causes some people to be left-handed? Is handedness a uniquely human trait? Are left-handers more likely than other people to be creative geniuses or to suffer cognitive disabilities? Historian Howard Kushner raises these and other questions in his new book,On the Other Hand.
Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease Science (IF 37.205) Pub Date : 2017-09-22 Lena F. Burbulla, Pingping Song, Joseph R. Mazzulli, Enrico Zampese, Yvette C. Wong, Sohee Jeon, David P. Santos, Judith Blanz, Carolin D. Obermaier, Chelsee Strojny, Jeffrey N. Savas, Evangelos Kiskinis, Xiaoxi Zhuang, Rejko Krüger, D. James Surmeier, Dimitri Krainc
Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson’s disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or α-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.
Interacting amino acid replacements allow poison frogs to evolve epibatidine resistance Science (IF 37.205) Pub Date : 2017-09-22 Rebecca D. Tarvin, Cecilia M. Borghese, Wiebke Sachs, Juan C. Santos, Ying Lu, Lauren A. O’Connell, David C. Cannatella, R. Adron Harris, Harold H. Zakon
Animals that wield toxins face self-intoxication. Poison frogs have a diverse arsenal of defensive alkaloids that target the nervous system. Among them is epibatidine, a nicotinic acetylcholine receptor (nAChR) agonist that is lethal at microgram doses. Epibatidine shares a highly conserved binding site with acetylcholine, making it difficult to evolve resistance yet maintain nAChR function. Electrophysiological assays of human and frog nAChR revealed that one amino acid replacement, which evolved three times in poison frogs, decreased epibatidine sensitivity but at a cost of acetylcholine sensitivity. However, receptor functionality was rescued by additional amino acid replacements that differed among poison frog lineages. Our results demonstrate how resistance to agonist toxins can evolve and that such genetic changes propel organisms toward an adaptive peak of chemical defense.
Observation of a large-scale anisotropy in the arrival directions of cosmic rays above 8 × 1018 eV Science (IF 37.205) Pub Date : 2017-09-22 The Pierre Auger Collaboration
Cosmic rays are atomic nuclei arriving from outer space that reach the highest energies observed in nature. Clues to their origin come from studying the distribution of their arrival directions. Using 3 × 104cosmic rays with energies above 8 × 1018electron volts, recorded with the Pierre Auger Observatory from a total exposure of 76,800 km2sr year, we determined the existence of anisotropy in arrival directions. The anisotropy, detected at more than a 5.2σ level of significance, can be described by a dipole with an amplitude ofpercent toward right ascension αd= 100 ± 10 degrees and declination δd=degrees.That direction indicates an extragalactic origin for these ultrahigh-energy particles.
Titanium isotopic evidence for felsic crust and plate tectonics 3.5 billion years ago Science (IF 37.205) Pub Date : 2017-09-22 Nicolas D. Greber, Nicolas Dauphas, Andrey Bekker, Matouš P. Ptáček, Ilya N. Bindeman, Axel Hofmann
Earth exhibits a dichotomy in elevation and chemical composition between the continents and ocean floor. Reconstructing when this dichotomy arose is important for understanding when plate tectonics started and how the supply of nutrients to the oceans changed through time. We measured the titanium isotopic composition of shales to constrain the chemical composition of the continental crust exposed to weathering and found that shales of all ages have a uniform isotopic composition. This can only be explained if the emerged crust was predominantly felsic (silica-rich) since 3.5 billion years ago, requiring an early initiation of plate tectonics. We also observed a change in the abundance of biologically important nutrients phosphorus and nickel across the Archean-Proterozoic boundary, which might have helped trigger the rise in atmospheric oxygen.
Angular momentum–induced delays in solid-state photoemission enhanced by intra-atomic interactions Science (IF 37.205) Pub Date : 2017-09-22 Fabian Siek, Sergej Neb, Peter Bartz, Matthias Hensen, Christian Strüber, Sebastian Fiechter, Miquel Torrent-Sucarrat, Vyacheslav M. Silkin, Eugene E. Krasovskii, Nikolay M. Kabachnik, Stephan Fritzsche, Ricardo Díez Muiño, Pedro M. Echenique, Andrey K. Kazansky, Norbert Müller, Walter Pfeiffer, Ulrich Heinzmann
Attosecond time-resolved photoemission spectroscopy reveals that photoemission from solids is not yet fully understood. The relative emission delays between four photoemission channels measured for the van der Waals crystal tungsten diselenide (WSe2) can only be explained by accounting for both propagation and intra-atomic delays. The intra-atomic delay depends on the angular momentum of the initial localized state and is determined by intra-atomic interactions. For the studied case of WSe2, the photoemission events are time ordered with rising initial-state angular momentum. Including intra-atomic electron-electron interaction and angular momentum of the initial localized state yields excellent agreement between theory and experiment. This has required a revision of existing models for solid-state photoemission, and thus, attosecond time-resolved photoemission from solids provides important benchmarks for improved future photoemission models.
The hidden simplicity of subduction megathrust earthquakes Science (IF 37.205) Pub Date : 2017-09-22 M.-A. Meier, J. P. Ampuero, T. H. Heaton
The largest observed earthquakes occur on subduction interfaces and frequently cause widespread damage and loss of life. Understanding the rupture behavior of megathrust events is crucial for earthquake rupture physics, as well as for earthquake early-warning systems. However, the large variability in behavior between individual events seemingly defies a description with a simple unifying model. Here we use three source time function (STF) data sets for subduction zone earthquakes, with moment magnitudeMw≥ 7, and show that such large ruptures share a typical universal behavior. The median STF is scalable between events with different sizes, grows linearly, and is nearly triangular. The deviations from the median behavior are multiplicative and Gaussian—that is, they are proportionally larger for larger events. Our observations suggest that earthquake magnitudes cannot be predicted from the characteristics of rupture onsets.
The growth pattern of Neandertals, reconstructed from a juvenile skeleton from El Sidrón (Spain) Science (IF 37.205) Pub Date : 2017-09-22 Antonio Rosas, Luis Ríos, Almudena Estalrrich, Helen Liversidge, Antonio García-Tabernero, Rosa Huguet, Hugo Cardoso, Markus Bastir, Carles Lalueza-Fox, Marco de la Rasilla, Christopher Dean
Ontogenetic studies help us understand the processes of evolutionary change. Previous studies on Neandertals have focused mainly on dental development and inferred an accelerated pace of general growth. We report on a juvenile partial skeleton (El Sidrón J1) preserving cranio-dental and postcranial remains. We used dental histology to estimate the age at death to be 7.7 years. Maturation of most elements fell within the expected range of modern humans at this age. The exceptions were the atlas and mid-thoracic vertebrae, which remained at the 5- to 6-year stage of development. Furthermore, endocranial features suggest that brain growth was not yet completed. The vertebral maturation pattern and extended brain growth most likely reflect Neandertal physiology and ontogenetic energy constraints rather than any fundamental difference in the overall pace of growth in this extinct human.
Teaching personal initiative beats traditional training in boosting small business in West Africa Science (IF 37.205) Pub Date : 2017-09-22 Francisco Campos, Michael Frese, Markus Goldstein, Leonardo Iacovone, Hillary C. Johnson, David McKenzie, Mona Mensmann
Standard business training programs aim to boost the incomes of the millions of self-employed business owners in developing countries by teaching basic financial and marketing practices, yet the impacts of such programs are mixed. We tested whether a psychology-based personal initiative training approach, which teaches a proactive mindset and focuses on entrepreneurial behaviors, could have more success. A randomized controlled trial in Togo assigned microenterprise owners to a control group (n= 500), a leading business training program (n= 500), or a personal initiative training program (n= 500). Four follow-up surveys tracked outcomes for firms over 2 years and showed that personal initiative training increased firm profits by 30%, compared with a statistically insignificant 11% for traditional training. The training is cost-effective, paying for itself within 1 year.
Infants make more attempts to achieve a goal when they see adults persist Science (IF 37.205) Pub Date : 2017-09-22 Julia A. Leonard, Yuna Lee, Laura E. Schulz
Persistence, above and beyond IQ, is associated with long-term academic outcomes. To look at the effect of adult models on infants’ persistence, we conducted an experiment in which 15-month-olds were assigned to one of three conditions: an Effort condition in which they saw an adult try repeatedly, using various methods, to achieve each of two different goals; a No Effort condition in which the adult achieved the goals effortlessly; or a Baseline condition. Infants were then given a difficult, novel task. Across an initial study and two preregistered experiments (N= 262), infants in the Effort condition made more attempts to achieve the goal than did infants in the other conditions. Pedagogical cues modulated the effect. The results suggest that adult models causally affect infants’ persistence and that infants can generalize the value of persistence to novel tasks.
PAF1 regulation of promoter-proximal pause release via enhancer activation Science (IF 37.205) Pub Date : 2017-09-22 Fei Xavier Chen, Peng Xie, Clayton K. Collings, Kaixiang Cao, Yuki Aoi, Stacy A. Marshall, Emily J. Rendleman, Michal Ugarenko, Patrick A. Ozark, Anda Zhang, Ramin Shiekhattar, Edwin R. Smith, Michael Q. Zhang, Ali Shilatifard
Gene expression in metazoans is regulated by RNA polymerase II (Pol II) promoter-proximal pausing and its release. Previously, we showed that Pol II–associated factor 1 (PAF1) modulates the release of paused Pol II into productive elongation. Here, we found that PAF1 occupies transcriptional enhancers and restrains hyperactivation of a subset of these enhancers. Enhancer activation as the result of PAF1 loss releases Pol II from paused promoters of nearby PAF1 target genes. Knockout of PAF1-regulated enhancers attenuates the release of paused Pol II on PAF1 target genes without major interference in the establishment of pausing at their cognate promoters. Thus, a subset of enhancers can primarily modulate gene expression by controlling the release of paused Pol II in a PAF1-dependent manner.
Global mRNA polarization regulates translation efficiency in the intestinal epithelium Science (IF 37.205) Pub Date : 2017-09-22 Andreas E. Moor, Matan Golan, Efi E. Massasa, Doron Lemze, Tomer Weizman, Rom Shenhav, Shaked Baydatch, Orel Mizrahi, Roni Winkler, Ofra Golani, Noam Stern-Ginossar, Shalev Itzkovitz
Asymmetric messenger RNA (mRNA) localization facilitates efficient translation in cells such as neurons and fibroblasts. However, the extent and importance of mRNA polarization in epithelial tissues are unclear. Here, we used single-molecule transcript imaging and subcellular transcriptomics to uncover global apical-basal intracellular polarization of mRNA in the mouse intestinal epithelium. The localization of mRNAs did not generally overlap protein localization. Instead, ribosomes were more abundant on the apical sides, and apical transcripts were consequently more efficiently translated. Refeeding of fasted mice elicited a basal-to-apical shift in polarization of mRNAs encoding ribosomal proteins, which was associated with a specific boost in their translation. This led to increased protein production, required for efficient nutrient absorption. These findings reveal a posttranscriptional regulatory mechanism involving dynamic polarization of mRNA and polarized translation.
Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9 Science (IF 37.205) Pub Date : 2017-09-22 Dong Niu, Hong-Jiang Wei, Lin Lin, Haydy George, Tao Wang, I-Hsiu Lee, Hong-Ye Zhao, Yong Wang, Yinan Kan, Ellen Shrock, Emal Lesha, Gang Wang, Yonglun Luo, Yubo Qing, Deling Jiao, Heng Zhao, Xiaoyang Zhou, Shouqi Wang, Hong Wei, Marc Güell, George M. Church, Luhan Yang
Xenotransplantation is a promising strategy to alleviate the shortage of organs for human transplantation. In addition to the concerns about pig-to-human immunological compatibility, the risk of cross-species transmission of porcine endogenous retroviruses (PERVs) has impeded the clinical application of this approach. We previously demonstrated the feasibility of inactivating PERV activity in an immortalized pig cell line. We now confirm that PERVs infect human cells, and we observe the horizontal transfer of PERVs among human cells. Using CRISPR-Cas9, we inactivated all of the PERVs in a porcine primary cell line and generated PERV-inactivated pigs via somatic cell nuclear transfer. Our study highlights the value of PERV inactivation to prevent cross-species viral transmission and demonstrates the successful production of PERV-inactivated animals to address the safety concern in clinical xenotransplantation.
Gordon Research Conferences Science (IF 37.205) Pub Date : 2017-09-22 American Association for the Advancement of Science
This issue ofScienceincludes the program of the 2018 GordonResearch Conferences.APDFof the program as it appears in this issue is availablehere; for more information on the meeting (including registration forms andinformation on accommodations), please visitwww.grc.org.
New Products Science (IF 37.205) Pub Date : 2017-09-22 American Association for the Advancement of Science
A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.
Liquid phase condensation in cell physiology and disease Science (IF 37.205) Pub Date : 2017-09-22 Yongdae Shin, Clifford P. Brangwynne
Phase transitions are ubiquitous in nonliving matter, and recent discoveries have shown that they also play a key role within living cells. Intracellular liquid-liquid phase separation is thought to drive the formation of condensed liquid-like droplets of protein, RNA, and other biomolecules, which form in the absence of a delimiting membrane. Recent studies have elucidated many aspects of the molecular interactions underlying the formation of these remarkable and ubiquitous droplets and the way in which such interactions dictate their material properties, composition, and phase behavior. Here, we review these exciting developments and highlight key remaining challenges, particularly the ability of liquid condensates to both facilitate and respond to biological function and how their metastability may underlie devastating protein aggregation diseases.
Loss of a mammalian circular RNA locus causes miRNA deregulation and affects brain function Science (IF 37.205) Pub Date : 2017-09-22 Monika Piwecka, Petar Glažar, Luis R. Hernandez-Miranda, Sebastian Memczak, Susanne A. Wolf, Agnieszka Rybak-Wolf, Andrei Filipchyk, Filippos Klironomos, Cledi Alicia Cerda Jara, Pascal Fenske, Thorsten Trimbuch, Vera Zywitza, Mireya Plass, Luisa Schreyer, Salah Ayoub, Christine Kocks, Ralf Kühn, Christian Rosenmund, Carmen Birchmeier, Nikolaus Rajewsky
Hundreds of circular RNAs (circRNAs) are highly abundant in the mammalian brain, often with conserved expression. Here we show that the circRNA Cdr1as is massively bound by the microRNAs (miRNAs) miR-7 and miR-671 in human and mouse brains. When theCdr1aslocus was removed from the mouse genome, knockout animals displayed impaired sensorimotor gating—a deficit in the ability to filter out unnecessary information—which is associated with neuropsychiatric disorders. Electrophysiological recordings revealed dysfunctional synaptic transmission. Expression of miR-7 and miR-671 was specifically and posttranscriptionally misregulated in all brain regions analyzed. Expression of immediate early genes such asFos, a direct miR-7 target, was enhanced inCdr1as-deficient brains, providing a possible molecular link to the behavioral phenotype. Our data indicate an in vivo loss-of-function circRNA phenotype and suggest that interactions between Cdr1as and miRNAs are important for normal brain function.
The microanatomic segregation of selection by apoptosis in the germinal center Science (IF 37.205) Pub Date : 2017-09-21 Christian T. Mayer, Anna Gazumyan, Ervin E. Kara, Alexander D. Gitlin, Jovana Golijanin, Charlotte Viant, Joy Pai, Thiago Y. Oliveira, Qiao Wang, Amelia Escolano, Max Medina-Ramirez, Rogier W. Sanders, Michel C. Nussenzweig
B cells undergo rapid cell division and affinity maturation in anatomically distinct sites in lymphoid organs called germinal centers (GCs). Homeostasis is maintained in part by B cell apoptosis. However, the precise contribution of apoptosis to GC biology and selection is not well defined. We developed apoptosis-indicator mice and used them to visualize, purify, and characterize dying GC B cells. Apoptosis is prevalent in the GC with up to half of all GC B cells dying every 6 hours. Moreover, programmed cell death is differentially regulated in the light zone (LZ) and the dark zone (DZ): LZ B cells die by default if they are not positively selected, whereas DZ cells die when their antigen receptors are damaged by activation-induced cytidine deaminase (AID).
Crystal structure of the human lysosomal mTORC1 scaffold complex and its impact on signaling Science (IF 37.205) Pub Date : 2017-09-21 Mariana E. G. de Araujo, Andreas Naschberger, Barbara G. Fürnrohr, Taras Stasyk, Theresia Dunzendorfer-Matt, Stefan Lechner, Stefan Welti, Leopold Kremser, Giridhar Shivalingaiah, Martin Offterdinger, Herbert H. Lindner, Lukas A. Huber, Klaus Scheffzek
LAMTOR (Late endosomal and lysosomal adaptor and mitogen activated protein kinase (MAPK) and mechanistic target of rapamycin (mTOR) activator) also known as “Ragulator,” controls the activity of mTOR complex 1 (mTORC1) on the lysosome. The crystal structure of LAMTOR consists of two roadblock/LC7 domain folded heterodimers wrapped and apparently held together by LAMTOR1, which assembles the complex on lysosomes. In addition, the Rag GTPases associated with the pentamer through their C-terminal domains, predefining the orientation for interaction with mTORC1. In vitro reconstitution and experiments with site directed mutagenesis defined the physiological importance of LAMTOR1 in assembling the remaining components to ensure fidelity of mTORC1 signaling. Functional data validated the impact of two short LAMTOR1 amino acid regions in recruitment and stabilization of the Rag GTPases.
Quantum acoustics with superconducting qubits Science (IF 37.205) Pub Date : 2017-09-21 Yiwen Chu, Prashanta Kharel, William H. Renninger, Luke D. Burkhart, Luigi Frunzio, Peter T. Rakich, Robert J. Schoelkopf
Mechanical objects have important practical applications in the fields of quantum information and metrology as quantum memories or transducers for measuring and connecting different types of quantum systems. The field of electromechanics is in pursuit of a robust and highly coherent device that couples motion to nonlinear quantum objects such as superconducting qubits. Here, we experimentally demonstrate a high-frequency bulk acoustic wave resonator that is strongly coupled to a superconducting qubit using piezoelectric transduction with a cooperativity of 260. We measure qubit and mechanical coherence times on the order of 10 microseconds. Our device requires only simple fabrication methods and provides controllable access to a multitude of phonon modes. We demonstrate quantum control and measurement on gigahertz phonons at the single quantum level.
Hanbury Brown and Twiss interferometry of single phonons from an optomechanical resonator Science (IF 37.205) Pub Date : 2017-09-21 Sungkun Hong, Ralf Riedinger, Igor Marinković, Andreas Wallucks, Sebastian G. Hofer, Richard A. Norte, Markus Aspelmeyer, Simon Gröblacher
Nano- and micromechanical devices have become a focus of attention as new solid-state quantum devices. Reliably generating non-classical states of their motion is of interest both for addressing fundamental questions about macroscopic quantum phenomena as well as for developing quantum technologies in the domains of sensing and transduction. We use quantum optical control techniques to conditionally generate single-phonon Fock states of a nanomechanical resonator. We perform a Hanbury Brown and Twiss type experiment that verifies the non-classical nature of the phonon state without requiring full state reconstruction. Our result establishes purely optical quantum control of a mechanical oscillator at the single phonon level.
MOF-derived cobalt nanoparticles catalyze a general synthesis of amines Science (IF 37.205) Pub Date : 2017-09-21 Rajenahally V. Jagadeesh, Kathiravan Murugesan, Ahmad S. Alshammari, Helfried Neumann, Marga-Martina Pohl, Jörg Radnik, Matthias Beller
The development of base metal catalysts for the synthesis of pharmaceutically relevant compounds remains an important goal of chemical research. Here, we report that cobalt nanoparticles encapsulated by a graphitic shell are broadly effective reductive amination catalysts. Their convenient and practical preparation entailed template assembly of cobalt-diamine-dicarboxylic acid metal organic frameworks on carbon and subsequent pyrolysis under inert atmosphere. The resulting stable and reusable catalysts were active for synthesis of primary, secondary, tertiary andN-methylamines (>140 examples). The reaction couples easily accessible carbonyl compounds (aldehydes, ketones) with ammonia, amines or nitro compounds and molecular hydrogen under industrially viable and scalable conditions, offering cost-effective access to numerous amines, amino acid derivatives, and more complex drug targets.
Imaging the halogen bond in self-assembled halogenbenzenes on silver Science (IF 37.205) Pub Date : 2017-09-14 Zhumin Han, Gregory Czap, Chi-lun Chiang, Chen Xu, Peter J. Wagner, Xinyuan Wei, Yanxing Zhang, Ruqian Wu, W. Ho
Halogens are among the most electronegative elements, and the variations in size and polarizability of halogens require different descriptions of the intermolecular bonds they form. Here we use the inelastic tunneling probe (itProbe) to acquire real-space imaging of intermolecular bonding structures in the two-dimensional self-assembly of halogenbenzene molecules on a metal surface. Direct visualization is obtained for the intermolecular attraction and the “windmill” pattern of bonding among the fully halogenated molecules. Our results provide hitherto missing understanding of the nature of the halogen bond.
Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer Science (IF 37.205) Pub Date : 2017-09-14 Jarno Drost, Ruben van Boxtel, Francis Blokzijl, Tomohiro Mizutani, Nobuo Sasaki, Valentina Sasselli, Joep de Ligt, Sam Behjati, Judith E. Grolleman, Tom van Wezel, Serena Nik-Zainal, Roland P. Kuiper, Edwin Cuppen, Hans Clevers
Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology, and hold diagnostic and prognostic value. Here, we develop a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR/Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed sub-cloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair geneMLH1is driven by replication errors and accurately models the mutation profiles observed in mismatch repair-deficient colorectal cancers. Application of this strategy to the cancer predisposition geneNTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germlineNTHL1mutations.
ZATT (ZNF451)–mediated resolution of topoisomerase 2 DNA-protein cross-links Science (IF 37.205) Pub Date : 2017-09-14 Matthew J. Schellenberg, Jenna Ariel Lieberman, Andrés Herrero-Ruiz, Logan R. Butler, Jason G. Williams, Ana M. Muñoz-Cabello, Geoffrey A. Mueller, Robert E. London, Felipe Cortés-Ledesma, R. Scott Williams
Topoisomerase 2 (TOP2) DNA transactions are essential for life, and proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a “split-SIM” SUMO2 engagement platform. These findings uncover a ZATT-TDP2–catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.
Mitotic transcription and waves of gene reactivation during mitotic exit Science (IF 37.205) Pub Date : 2017-09-14 Katherine C. Palozola, Greg Donahue, Hong Liu, Gregory R. Grant, Justin S. Becker, Allison Cote, Hongtao Yu, Arjun Raj, Kenneth S. Zaret
Although the genome is generally thought to be transcriptionally silent during mitosis, technical limitations have prevented sensitive mapping of transcription during mitosis and mitotic exit. Thus, the means by which the interphase expression pattern is transduced to daughter cells have been unclear. We used 5-ethynyluridine to pulse-label transcripts during mitosis and mitotic exit and find that many genes exhibit transcription during mitosis, as confirmed by FITC-UTP labeling, RNA FISH, and RT-qPCR. The first round of transcription immediately following mitosis primarily activates genes involved in the growth and rebuilding of daughter cells, rather than cell type-specific functions. We propose that the cell’s transcription pattern is largely retained at a low level through mitosis, whereas the amplitude of transcription observed in interphase is re-established during mitotic exit.
DNA sequence–directed shape change of photopatterned hydrogels via high-degree swelling Science (IF 37.205) Pub Date : 2017-09-15 Angelo Cangialosi, ChangKyu Yoon, Jiayu Liu, Qi Huang, Jingkai Guo, Thao D. Nguyen, David H. Gracias, Rebecca Schulman
Shape-changing hydrogels that can bend, twist, or actuate in response to external stimuli are critical to soft robots, programmable matter, and smart medicine. Shape change in hydrogels has been induced by global cues, including temperature, light, or pH. Here we demonstrate that specific DNA molecules can induce 100-fold volumetric hydrogel expansion by successive extension of cross-links. We photopattern up to centimeter-sized gels containing multiple domains that undergo different shape changes in response to different DNA sequences. Experiments and simulations suggest a simple design rule for controlled shape change. Because DNA molecules can be coupled to molecular sensors, amplifiers, and logic circuits, this strategy introduces the possibility of building soft devices that respond to diverse biochemical inputs and autonomously implement chemical control programs.
Highly efficient electrocaloric cooling with electrostatic actuation Science (IF 37.205) Pub Date : 2017-09-15 Rujun Ma, Ziyang Zhang, Kwing Tong, David Huber, Roy Kornbluh, Yongho Sungtaek Ju, Qibing Pei
Solid-state refrigeration offers potential advantages over traditional cooling systems, but few devices offer high specific cooling power with a high coefficient of performance (COP) and the ability to be applied directly to surfaces. We developed a cooling device with a high intrinsic thermodynamic efficiency using a flexible electrocaloric (EC) polymer film and an electrostatic actuation mechanism. Reversible electrostatic forces reduce parasitic power consumption and allow efficient heat transfer through good thermal contacts with the heat source or heat sink. The EC device produced a specific cooling power of 2.8 watts per gram and a COP of 13. The new cooling device is more efficient and compact than existing surface-conformable solid-state cooling technologies, opening a path to using the technology for a variety of practical applications.
Soft x-ray excitonics Science (IF 37.205) Pub Date : 2017-09-15 A. Moulet, J. B. Bertrand, T. Klostermann, A. Guggenmos, N. Karpowicz, E. Goulielmakis
The dynamic response of excitons in solids is central to modern condensed-phase physics, material sciences, and photonic technologies. However, study and control have hitherto been limited to photon energies lower than the fundamental band gap. Here we report application of attosecond soft x-ray and attosecond optical pulses to study the dynamics of core-excitons at the L2,3edge of Si in silicon dioxide (SiO2). This attosecond x-ray absorption near-edge spectroscopy (AXANES) technique enables direct probing of the excitons’ quasiparticle character, tracking of their subfemtosecond relaxation, the measurement of excitonic polarizability, and observation of dark core-excitonic states. Direct measurement and control of core-excitons in solids lay the foundation of x-ray excitonics.
Fabrication of fillable microparticles and other complex 3D microstructures Science (IF 37.205) Pub Date : 2017-09-15 Kevin J. McHugh, Thanh D. Nguyen, Allison R. Linehan, David Yang, Adam M. Behrens, Sviatlana Rose, Zachary L. Tochka, Stephany Y. Tzeng, James J. Norman, Aaron C. Anselmo, Xian Xu, Stephanie Tomasic, Matthew A. Taylor, Jennifer Lu, Rohiverth Guarecuco, Robert Langer, Ana Jaklenec
Three-dimensional (3D) microstructures created by microfabrication and additive manufacturing have demonstrated value across a number of fields, ranging from biomedicine to microelectronics. However, the techniques used to create these devices each have their own characteristic set of advantages and limitations with regards to resolution, material compatibility, and geometrical constraints that determine the types of microstructures that can be formed. We describe a microfabrication method, termed StampEd Assembly of polymer Layers (SEAL), and create injectable pulsatile drug-delivery microparticles, pH sensors, and 3D microfluidic devices that we could not produce using traditional 3D printing. SEAL allows us to generate microstructures with complex geometry at high resolution, produce fully enclosed internal cavities containing a solid or liquid, and use potentially any thermoplastic material without processing additives.
Distinct phases of Polycomb silencing to hold epigenetic memory of cold in Arabidopsis Science (IF 37.205) Pub Date : 2017-09-15 Hongchun Yang, Scott Berry, Tjelvar S. G. Olsson, Matthew Hartley, Martin Howard, Caroline Dean
Gene silencing by Polycomb complexes is central to eukaryotic development. Cold-induced epigenetic repression ofFLOWERING LOCUS C(FLC) in the plantArabidopsisprovides an opportunity to study initiation and maintenance of Polycomb silencing. Here, we show that a subset of Polycomb repressive complex 2 factors nucleate silencing in a small region withinFLC, locally increasing H3K27me3 levels. This nucleation confers a silenced state that is metastably inherited, with memory held in the local chromatin. Metastable memory is then converted to stable epigenetic silencing through separate Polycomb factors, which spread across the locus after cold to enlarge the domain that contains H3K27me3. Polycomb silencing atFLCthus has mechanistically distinct phases, which involve specialization of distinct Polycomb components to deliver first metastable then long-term epigenetic silencing.
DNA replication–coupled histone modification maintains Polycomb gene silencing in plants Science (IF 37.205) Pub Date : 2017-09-15 Danhua Jiang, Frédéric Berger
Propagation of patterns of gene expression through the cell cycle requires prompt restoration of epigenetic marks after the twofold dilution caused by DNA replication. Here we show that the transcriptional repressive mark H3K27me3 (histone H3 lysine 27 trimethylation) is restored in replicating plant cells through DNA replication–coupled modification of histone variant H3.1. Plants evolved a mechanism for efficient K27 trimethylation on H3.1, which is essential for inheritance of the silencing memory from mother to daughter cells. We illustrate how this mechanism establishes H3K27me3-mediated silencing during the developmental transition to flowering. Our study reveals a mechanism responsible for transmission of H3K27me3 in plant cells through cell divisions, enabling H3K27me3 to function as an epigenetic mark.
Thirst-associated preoptic neurons encode an aversive motivational drive Science (IF 37.205) Pub Date : 2017-09-15 William E. Allen, Laura A. DeNardo, Michael Z. Chen, Cindy D. Liu, Kyle M. Loh, Lief E. Fenno, Charu Ramakrishnan, Karl Deisseroth, Liqun Luo
Water deprivation produces a drive to seek and consume water. How neural activity creates this motivation remains poorly understood. We used activity-dependent genetic labeling to characterize neurons activated by water deprivation in the hypothalamic median preoptic nucleus (MnPO). Single-cell transcriptional profiling revealed that dehydration-activated MnPO neurons consist of a single excitatory cell type. After optogenetic activation of these neurons, mice drank water and performed an operant lever-pressing task for water reward with rates that scaled with stimulation frequency. This stimulation was aversive, and instrumentally pausing stimulation could reinforce lever-pressing. Activity of these neurons gradually decreased over the course of an operant session. Thus, the activity of dehydration-activated MnPO neurons establishes a scalable, persistent, and aversive internal state that dynamically controls thirst-motivated behavior.
Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine Science (IF 37.205) Pub Date : 2017-09-15 Leore T. Geller, Michal Barzily-Rokni, Tal Danino, Oliver H. Jonas, Noam Shental, Deborah Nejman, Nancy Gavert, Yaara Zwang, Zachary A. Cooper, Kevin Shee, Christoph A. Thaiss, Alexandre Reuben, Jonathan Livny, Roi Avraham, Dennie T. Frederick, Matteo Ligorio, Kelly Chatman, Stephen E. Johnston, Carrie M. Mosher, Alexander Brandis, Garold Fuks, Candice Gurbatri, Vancheswaran Gopalakrishnan, Michael Kim, Mark W. Hurd, Matthew Katz, Jason Fleming, Anirban Maitra, David A. Smith, Matt Skalak, Jeffrey Bu, Monia Michaud, Sunia A. Trauger, Iris Barshack, Talia Golan, Judith Sandbank, Keith T. Flaherty, Anna Mandinova, Wendy S. Garrett, Sarah P. Thayer, Cristina R. Ferrone, Curtis Huttenhower, Sangeeta N. Bhatia, Dirk Gevers, Jennifer A. Wargo, Todd R. Golub, Ravid Straussman
Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDDLexpression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.
A Neolithic expansion, but strong genetic structure, in the independent history of New Guinea Science (IF 37.205) Pub Date : 2017-09-15 Anders Bergström, Stephen J. Oppenheimer, Alexander J. Mentzer, Kathryn Auckland, Kathryn Robson, Robert Attenborough, Michael P. Alpers, George Koki, William Pomat, Peter Siba, Yali Xue, Manjinder S. Sandhu, Chris Tyler-Smith
New Guinea shows human occupation since ~50 thousand years ago (ka), independent adoption of plant cultivation ~10 ka, and great cultural and linguistic diversity today. We performed genome-wide single-nucleotide polymorphism genotyping on 381 individuals from 85 language groups in Papua New Guinea and find a sharp divide originating 10 to 20 ka between lowland and highland groups and a lack of non–New Guinean admixture in the latter. All highlanders share ancestry within the last 10 thousand years, with major population growth in the same period, suggesting population structure was reshaped following the Neolithic lifestyle transition. However, genetic differentiation between groups in Papua New Guinea is much stronger than in comparable regions in Eurasia, demonstrating that such a transition does not necessarily limit the genetic and linguistic diversity of human societies.
Technology Feature | Agreeable antibodies: Antibody validation challenges and solutions Science (IF 37.205) Pub Date : 2017-09-15 Alan Dove
Commercially produced antibodies have become workhorses of basic research, but opaque supply chains, a lack of clear quality standards, and scientists' complacency have turned antibody-based experiments into potential disaster zones. Several strategies can help researchers navigate past these pitfalls.Read the Feature (Full-Text HTML)Read the Feature (PDF)Read New Products (PDF)
New Products Science (IF 37.205) Pub Date : 2017-09-15 American Association for the Advancement of Science
A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.
Webinar | Deciphering cancer: Understanding tumor invasion and the metastatic microenvironment Science (IF 37.205) Pub Date : 2017-09-15 David C. Lyden, Shahin Rafii
Tumor metastasis is a multistep process that includes stimulation of angiogenesis, intravasation of tumor cells into blood or lymphatic vessels, and subsequent engraftment and extravasation to peripheral tissues where secondary tumors are seeded. It is known that metastatic progression is driven by mutational and epigenetic changes in tumor cells, but more recent efforts have focused on the evolving interplay between the tumor cell and the tumor microenvironment (TME) during invasion and transition from micrometastasis to macrometastasis. Whether the tumor cell or the subverted vascular niche/premetastatic niche is the driver of TME evolution remains the subject of debate. This webinar examines the role of tumor-secreted factors, including exosomes and tumor vascular niche—derived protumorigenic factors in tumor—environment interactions, and their implications for development of therapeutic interventions to arrest metastasis.View the Webinar
Sponsored Collection | SPReading the word: The importance of binding kinetics Science (IF 37.205) Pub Date : 2017-09-15 American Association for the Advancement of Science
Download high-res imageOpen in new tabDownload PowerpointFans of the sci-fi seriesStar Trekare familiar with the show's fictional "tricorders," handheld devices used for sensor scanning and data analysis and recording. Yet these futuristic instruments are now, in a sense, entering the real world due to the advent of biosensors, devices that transform the detection of biological elements—antibodies, nucleic acids, cell receptors, enzymes, among others—into signals (e.g., optical, electrochemical) that can be more easily measured and quantified. The technology behind this modern-day measuring equipment is surface plasmon resonance (SPR), a process through which electrons on a metal surface are excited by a polarized light source, creating charge-density waves called plasmons. These plasmons then bend the light at a specific angle (known as the resonance angle) that is picked up through a detector. As molecules bind and dissociate from the metal surface, the resonance angle changes, giving an interaction profile (including binding kinetics, specificity, concentration, and affinity) that is recorded in real time. The possibilities for this technology include proteomics, immunogenicity, and drug discovery, but really are limitless. However, the best use for SPR is precision medicine. This tool could help to more quickly identify molecules or compounds that could aid in treatment of diseases. Conversely, it could also help pinpoint which patients would respond best to a particular drug or vaccine. Included in this booklet are articles fromScience,Science Translational Medicine, andScience Signalingthat detail the prospects for SPR technology.SPReading the word: The importance of binding kinetics ( PDF, 4.71 MB )View the online versionThis special supplement brought to you by theScience/AAAS Custom Publishing Office.
The form and function of channelrhodopsin Science (IF 37.205) Pub Date : 2017-09-15 Karl Deisseroth, Peter Hegemann
Channelrhodopsins are light-gated ion channels that, via regulation of flagellar function, enable single-celled motile algae to seek ambient light conditions suitable for photosynthesis and survival. These plant behavioral responses were initially investigated more than 150 years ago. Recently, major principles of function for light-gated ion channels have been elucidated by creating channelrhodopsins with kinetics that are accelerated or slowed over orders of magnitude, by discovering and designing channelrhodopsins with altered spectral properties, by solving the high-resolution channelrhodopsin crystal structure, and by structural model–guided redesign of channelrhodopsins for altered ion selectivity. Each of these discoveries not only revealed basic principles governing the operation of light-gated ion channels, but also enabled the creation of new proteins for illuminating, via optogenetics, the fundamentals of brain function.
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