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Preview: Science: Current IssueScience: This Week's NewsThis Week in ScienceEditors' ChoiceNetWatchScience Magazine PodcastScienceNOW

Science: Current Issue



The best in science news, commentary, and research



Published: 2016-12-01T13:53:11-05:00

 









[Review] Intracellular innate immune surveillance devices in plants and animals

2016-12-02

Multicellular eukaryotes coevolve with microbial pathogens, which exert strong selective pressure on the immune systems of their hosts. Plants and animals use intracellular proteins of the nucleotide-binding domain, leucine-rich repeat (NLR) superfamily to detect many types of microbial pathogens. The NLR domain architecture likely evolved independently and convergently in each kingdom, and the molecular mechanisms of pathogen detection by plant and animal NLRs have long been considered to be distinct. However, microbial recognition mechanisms overlap, and it is now possible to discern important key trans-kingdom principles of NLR-dependent immune function. Here, we attempt to articulate these principles. We propose that the NLR architecture has evolved for pathogen-sensing in diverse organisms because of its utility as a tightly folded “hair trigger” device into which a virtually limitless number of microbial detection platforms can be integrated. Recent findings suggest means to rationally design novel recognition capabilities to counter disease. Authors: Jonathan D. G. Jones, Russell E. Vance, Jeffery L. Dangl



[Editorial] A comprehensive nuclear test ban

2016-12-02

A permanent end to nuclear explosive testing, combined with sustained reliable deterrence, is in the national security interest of the United States and its allies and friends. The next U.S. Administration and the Congress should revisit the Comprehensive Nuclear Test Ban Treaty (CTBT) in view of current realities and work together toward enhanced security through ratification and an international push for entry into force. Author: Ernest J. Moniz



[In Brief] News at a glance

2016-12-02

In science news around the world, the coral die-off in 2016 in the Great Barrier Reef because of bleaching reaches a new record, results of the 2015 Trends in International Mathematics and Science Study show that East Asian students still lead the world in math and science scores, a widely watched candidate drug for Alzheimer's disease fails, a cancer immunotherapy trial claims two more lives on top of three earlier this year, and more. Also, U.S. President-elect Donald Trump names his nominees to head the Department of Health and Human Services and the Department of Education. And ant "kisses" can transfer not only nutrients, but also hormones that help shape their colonies' long-term fate.



[In Depth] Dam-building threatens Mekong fisheries

2016-12-02

Laos and its neighbors hungry for electric power are embarking on a dam-building spree on the Mekong River and on major tributaries that threatens to trigger a food security crisis. By blocking migration routes and cutting sediment flow to the Mekong delta, the projects could wipe out more than a third of the lower Mekong Basin's annual haul of river fish—a serious blow to the region's 60 million people. Hoping to forestall catastrophe, environmentalists and scientists are pressing the hydropower companies to incorporate "fish-friendly" turbines, ladders, and locks for migratory fish into their dam designs. At a meeting last month in Vientiane to discuss fish-passage approaches, some scientists saw reason for optimism. But others scoffed at the mitigation plans and believe that the only way to spare the fisheries is to drop some of the projects. Author: Richard Stone



[In Depth] Congress votes on sweeping biomedical bill

2016-12-02

Congress this week began voting on a sweeping biomedical innovation bill that includes nearly $5 billion in dedicated funding for a trio of major research initiatives at the National Institutes of Health (NIH). The bill also includes measures to speed the approval of new drugs and medical devices by the Food and Drug Administration, and it would create a mechanism for catalyzing efforts to streamline federal regulations that universities and academic researchers regard as burdensome. The bipartisan bill, known as the 21st Century Cures Act, is the culmination of more than 2 years of lobbying by research, patient, and industry groups, and extensive negotiations between members of the Senate and the House of Representatives. The bill includes a long list of largely uncontroversial NIH provisions, including calls for the agency to produce a comprehensive strategic plan, set up a special initiative for young scientists, establish a prize to incentivize certain kinds of research, and take new steps to encourage data sharing and ensure the reproducibility of NIH-funded research. And research lobbyists are delighted with provisions that set aside $4.8 billion over the next 10 years for three NIH initiatives: $1.4 billion for Obama's Precision Medicine Initiative, $1.8 billion for Vice President Joe Biden's cancer moonshot, and $1.6 billion for the White House's Brain Research through Advancing Innovative Neurotechnologies Initiative. The bill also provides $30 million over 3 years for regenerative medicine research using adult stem cells. But biomedical research advocates are worried how the funding may ultimately play out, and other bureaucratic provisions they say could be burdensome. Authors: Jocelyn Kaiser, Jeffrey Mervis, Kelly Servick



[In Depth] Hubble uses galactic lens to study universe's first stars

2016-12-02

In a just-completed observing program, astronomers fitted the Hubble Space Telescope with the cosmic equivalent of a telephoto lens. Their goal was to scour the oldest and most distant reaches of the cosmos for the small, dim galaxies that probably held most of the first stars. Hubble's vision isn't keen enough, so its handlers aimed it at six massive galaxy clusters—groupings of hundreds or thousands of galaxies—hoping for a boost from a phenomenon, gravitational lensing, originally predicted by Albert Einstein. With their masses bending light from background objects, the thinking went, these clusters would bring fainter galaxies into view. Astronomers are just starting to pour over data from this Frontier Fields program, but early results promised to shed light on the so-called epoch of reionization—the time when the universe was less than a billion years old and something blasted the neutral gas scattered through space after the big bang, stripping away its electrons. Author: Daniel Clery



[In Depth] One year later, Zika scientists prepare for a long war

2016-12-02

The World Health Organization recently announced that the Zika epidemic is no longer a Public Health Emergency of International Concern, a designation reserved for acute threats that Zika received in February. But the decision only means that Zika has evolved from an emergency to another long-term public health challenge. The Zika virus is now firmly entrenched in Latin America, which is already battling several other mosquito-borne diseases. Meanwhile, Zika vaccines aren't available yet, and fundamental gaps remain in scientists' knowledge of the virus and the risk of microcephaly and other birth defects that it poses. Perhaps the biggest question is also the most difficult to answer: Why have the effects of Zika been so pronounced in northeastern Brazil? Author: Gretchen Vogel



[In Depth] Energy pulses reveal possible new state of memory

2016-12-02

Memory researchers have shone light into a cognitive limbo. A new memory—the name of someone you've just met, for example—is held for seconds in so-called working memory, as your brain's neurons continue to fire. If the person is important to you, the name will over a few days enter your long-term memory, preserved by permanently altered neural connections. But where does it go during the in-between hours, when it has left your standard working memory and is not yet embedded in long-term memory? To figure this out, a research team resurrects memories from this limbo. Their observations point to a new form of working memory, which they dub prioritized long-term memory, that exists without elevated neural activity. Consistent with other recent work, the study suggests that information can somehow be held among the synapses that connect neurons, even after conventional working memory has faded. This new memory state could have a range of practical implications, from helping college students learn more efficiently to assisting people with memory-related neurological conditions such as amnesia, epilepsy, and schizophrenia. Author: Jessica Boddy



[Feature] Quest for qubits

2016-12-02

Building a quantum computer has gone from a far-off dream of a few university scientists to an immediate goal for some of the world's biggest companies. Tech giants Intel, Microsoft, IBM, and Google are all plowing tens of millions of dollars into quantum computing, which aims to harness quantum mechanics to vastly accelerate computation. Yet the contenders are betting on different technological horses: No one yet knows what type of quantum logic bit, or qubit, will power a practical quantum computer. Google, often considered the field's leader, has signaled its choice: tiny, superconducting circuits. Its group has built a nine-qubit machine and hopes to scale up to 49 within a year—an important threshold. At about 50 qubits, many say a quantum computer could achieve "quantum supremacy" and do something beyond the ken of a classical computer, such as simulating molecular structures in chemistry and materials science, or solving problems in cryptography. Small startup company ionQ, a decided underdog, is sticking with its preferred technology: trapped ions. Author: Gabriel Popkin



[Feature] Bringing legends to life

2016-12-02

Using ancient DNA techniques, geneticist Li Hui of Fudan University in Shanghai, China, hopes to demonstrate that some cherished Chinese myths are grounded in reality. His current passion is an exploration of the Three Sovereigns. Chinese credit the legendary sage-kings with laying the foundations of their culture: inventing silk and medicine, for instance, and fashioning China's written characters. Li says he has gleaned support for the Three Sovereigns legend from a vast database of DNA samples gathered around China. His team's studies of the Y chromosome—the male sex chromosome—trace about half of modern Chinese men back to three ancient groups. Li's quest has won cautious praise from some scholars. Others see a skein of nationalism running through the attempt to establish a cohesive Chinese culture predating China's first dynasty, the Xia. Author: Kathleen McLaughlin



[Policy Forum] Reforming the U.S. coal leasing program

2016-12-02

About 40% of all coal mined in the United States is extracted from lands owned by the federal government, under leases managed by the U.S. Department of the Interior (DOI). Burning that coal accounts for 13% of U.S. energy-related greenhouse gas (GHG) emissions (1). With the largest and lowest-cost reserves in the United States, federal coal alone—estimated at nearly 10% of the world's known reserves—has potential to contribute substantially to atmospheric CO2 concentrations (2). In response to calls for reform, DOI has issued a moratorium on new leases while it develops a Programmatic Environmental Impact Statement to guide the first major reform of the program since 1982. We review existing knowledge of key issues relevant to reform, highlighting the social costs of coal extraction, the extent of substitution away from federal coal induced by raising additional leasing revenue, the lack of competition in the leasing auctions, and the incentives inherent in the current leasing program structure. We then turn to critical areas of research that can be done in the near term and would contribute to more informed debate and policy development. Authors: Kenneth Gillingham, James Bushnell, Meredith Fowlie, Michael Greenstone, Charles Kolstad, Alan Krupnick, Adele Morris, Richard Schmalensee, James Stock



[Perspective] As the bat flies

2016-12-02

The importance of predicting the timing and location of infectious disease emergence events from animal into human populations is highlighted by the effect of Ebola virus in West Africa. Such predictions are, however, usually hampered by a dearth of data. In a recent analysis of rabies viruses derived from vampire bats (see the photo) in Peru, Streicker et al. show that with sufficient data on both pathogen and host and with accurate models, predictions can be made to inform surveillance and public health efforts (1). Author: David T. S. Hayman



[Perspective] Spying on the neighbors' pool

2016-12-02

The structure and properties of the proton in water are of fundamental importance in many areas of chemistry and biology. The high mobility of the proton in an aqueous solution is understood in terms of its “hopping” between neighboring water molecules, as suggested by the two-century-old Grotthuss mechanism. The barrier for this process intimately depends on the proton's surrounding environment, which is manifested by the connectivity of the immediate hydrogen-bonding network as well as its dynamics caused by thermal fluctuations. On page 1131 of this issue, Wolke et al. (1) shed new light on the role that the proton's water neighbors play toward facilitating positive charge translocation within a hydrogen-bonded network in a cold water cluster. Author: Sotiris S. Xantheas



[Perspective] Galaxy formation through cosmic recycling

2016-12-02

Extremely massive galaxies are seen in the young universe, but their presence is puzzling because we do not yet understand how they became so massive so quickly. How do they get enough fuel to form stars so rapidly? The raw fuel for forming stars is cold molecular gas, and although this gas is common within young galaxies (1), we do not know how it is replenished once the first reservoirs are converted into stars. On page 1128 of this issue, Emonts et al. (2) report observations that may provide our first clue to this fueling problem. They have detected a giant reservoir of recycled molecular gas that is replenishing the fuel supply of one of the most massive galaxies in the young universe. Author: Nina Hatch



[Perspective] Metabolic cues for hematopoietic stem cells

2016-12-02

Hematopoietic stem cells (HSCs) are at the helm of the hierarchically organized hematopoietic system that ensures the lifelong production of all blood cells. HSCs depend on metabolic cues to secure their protective quiescent status and to enable rapid activation and replenishment of the blood system in response to stressful situations such as infections, excessive bleeding, or chemotherapy-induced myeloablation (1–3). On pages 1156 and 1152 of this issue, Ito et al. (4) and Taya et al. (5), respectively, uncover important roles for the degradation of defective mitochondria (mitophagy) and the amino acid valine in HSC maintenance and function. Authors: Pia Sommerkamp, Andreas Trumpp



[Perspective] Can T cells be too exhausted to fight back?

2016-12-02

When T cells are persistently activated by antigen, such as during chronic infection or in cancer, they can become functionally incapable of performing their effector activities, a condition called T cell exhaustion. Exhaustion therefore thwarts optimal immune control of infection and tumors. There is a need to learn more about the molecular factors that drive T cell exhaustion and just how malleable T cell immunity is once exhaustion is established. On pages 1165 and 1160 of this issue, Sen et al. (1) and Pauken et al. (2), respectively, demonstrate that T cell exhaustion represents a stable differentiation state, underpinned by the apparently irreversible installation of an exhaustion-specific genetic landscape. This implies that perhaps in a majority of cases of persistent immune activation, T cells are too exhausted to fight back against cancer or pathogens. Authors: Stephen J. Turner, Brendan E. Russ



[Perspective] When stop makes sense

2016-12-02

In the age of computational biology, it is easy to envision the genetic code as a set of immutable instructions that the cell follows without exception. The recent discovery of ciliate (1, 2) and trypanosomatid (3) species in which all three stop codons, which normally act to terminate protein translation by the ribosome, encode amino acids instead is a reminder that decoding the information in messenger RNA (mRNA) depends on molecular factors that we do not entirely understand. In these organisms, stop codons specify amino acids by default, and termination of mRNA translation only occurs in close proximity to the polyadenylate [poly(A)] tail. How do these species differentiate “true” stop codons from identical ones that encode amino acids? The answers to this puzzle may provide insights into translation termination and gene regulation in all eukaryotes. Authors: Boris Zinshteyn, Rachel Green



[Retrospective] Ralph J. Cicerone (1943–2016)

2016-12-02

Ask which university in the United States does the most to improve career outcomes for low-income students, and the University of California (UC), Irvine, comes out on top, based on surveys. This is the fertile environment for teaching and research that Ralph J. Cicerone, as chancellor (1998–2005), brought to international prominence. Walk around the National Academy of Sciences in Washington, DC, and hear the echoes of more than a century and a half of lofty debate among the nation's most respected scientists. This is the sanctuary for science that Cicerone, as president (2005–2016), lovingly nurtured and enhanced. Authors: John P. Holdren, Marcia K. McNutt



[Essay] Trial and error

2016-12-02

We are all prediction-making machines. Granted, our predictions are often wrong—as the old saying goes, “It's tough to make predictions—especially about the future.” But even wrong predictions serve a purpose: They help us learn. Each time we make a choice, we predict the outcome of that choice. When the outcome matches our prediction, there is no need to learn. When the outcome is unexpected, however, we update our predictions, hoping to do better next time. Author: Neir Eshel



[Essay] The future of bionic dynamos

2016-12-02

Millions of lives rely on implantable medical devices. At present, the power sources (typically batteries) for such devices are rigid and bulky and must be changed frequently. Users are often forced to undergo a surgical procedure each time the battery needs to be changed, which are accompanied by health risks and high costs. Author: Canan Dagdeviren



[Essay] Retracing embryological fate

2016-12-02

Mammalian development is a beautifully orchestrated process of cell division and differentiation during which the various cell lineages arise that form an organism. The precise nature, origin, and fate of these lineages remain a mystery in humans and in other mammals. In addition to illuminating fundamental developmental biology, mapping human cell lineages may offer insights into a range of physiological and pathological processes, such as stem cell development, congenital diseases, and childhood cancer (1). Author: Sam Behjati



[Essay] Passing the point of no return

2016-12-02

In the field of ecology, regime shifts are massive changes in function and character that occur when an ecosystem passes a tipping point. Regime shifts sometimes have severe consequences for human well-being through losses of ecosystem services, including desertification in arid regions and marine fisheries collapses (1, 2). These changes are difficult to predict and sometimes impossible to reverse (2). For these reasons, understanding how to anticipate and prevent regime shifts is one of the most important challenges faced by environmental scientists (1–3). Author: David Seekell



[Book Review] The intelligent invertebrate

2016-12-02

Octopi are elusive creatures with notoriously complex behavior. They often acquiesce to carefully controlled experiments, but little is known about their cognitive abilities or the exact nature of their social interactions. With Other Minds, Peter Godfrey-Smith has set himself a double challenge: (i) putting together what is known about octopi behavior and cognition and (ii) showing why this information challenges our philosophical and scientific conceptions of the mind. Author: Ophelia Deroy



[Book Review] Arrested development

2016-12-02

The discovery, development, and registration of new drugs is a complicated and protracted process, often taking more than 10 years. It is also quite expensive, with an estimated cost per new drug in excess of $1 billion. In A Prescription for Change, Michael Kinch traces the history of the pharmaceutical and biotechnology industriesand describes the evolution of the scientific, regulatory, social, and marketing forces that are compromising contemporary drug development efforts. Author: George Painter



[Letter] Nuclear power: Serious risks

2016-12-02

Authors: Philip Johnstone, Benjamin K. Sovacool, Gordon MacKerron, Andy Stirling



[Letter] Nuclear power: Deployment speed

2016-12-02

Author: Amory B. Lovins



[Letter] Nuclear power: Deployment speed—Response

2016-12-02

Authors: Junji Cao, Armond Cohen, James Hansen, Richard Lester, Per Peterson, Staffan A. Qvist, Hong jie Xu



[This Week in Science] How new particles form

2016-12-02

Author: H. Jesse Smith






[This Week in Science] Running interference

2016-12-02

Author: Yevgeniya Nusinovich









[This Week in Science] Zika virus is fit to be tied

2016-12-02

Author: Kristen L. Mueller






[This Week in Science] Protecting by changing the code

2016-12-02

Author: Kristen L. Mueller









[This Week in Science] Tie me up, cut me down

2016-12-02

Author: Pamela J. Hines












[This Week in Science] The epigenetics of exhaustion

2016-12-02

Author: Kristen L. Mueller



[This Week in Science] How bats spread viruses

2016-12-02

Author: Julia Fahrenkamp-Uppenbrink



[This Week in Science] Letting SLE-Ping plaques lie

2016-12-02

Author: Angela Colmone



[Editors' Choice] Acquiring the genes to digest wood

2016-12-02

Author: Laura M. Zahn



[Editors' Choice] Targeting tip growth

2016-12-02

Author: Pamela J. Hines



[Editors' Choice] Getting an UPR hand on recovERy

2016-12-02

Author: Stella M. Hurtley



[Editors' Choice] Neuron development in human embryos

2016-12-02

Author: Sarah Harrison



[Editors' Choice] Keeping tissue layers separate

2016-12-02

Author: Sarah Harrison






[Editors' Choice] Side effects for placebo poppers

2016-12-02

Author: Caroline Ash



[Research Article] Crystal structures of a group II intron lariat primed for reverse splicing

2016-12-02

The 2′-5′ branch of nuclear premessenger introns is believed to have been inherited from self-splicing group II introns, which are retrotransposons of bacterial origin. Our crystal structures at 3.4 and 3.5 angstrom of an excised group II intron in branched (“lariat”) form show that the 2′-5′ branch organizes a network of active-site tertiary interactions that position the intron terminal 3′-hydroxyl group into a configuration poised to initiate reverse splicing, the first step in retrotransposition. Moreover, the branchpoint and flanking helices must undergo a base-pairing switch after branch formation. A group II–based model of the active site of the nuclear splicing machinery (the spliceosome) is proposed. The crucial role of the lariat conformation in active-site assembly and catalysis explains its prevalence in modern splicing. Authors: Maria Costa, Hélène Walbott, Dario Monachello, Eric Westhof, François Michel



[Research Article] Global atmospheric particle formation from CERN CLOUD measurements

2016-12-02

Fundamental questions remain about the origin of newly formed atmospheric aerosol particles because data from laboratory measurements have been insufficient to build global models. In contrast, gas-phase chemistry models have been based on laboratory kinetics measurements for decades. We built a global model of aerosol formation by using extensive laboratory measurements of rates of nucleation involving sulfuric acid, ammonia, ions, and organic compounds conducted in the CERN CLOUD (Cosmics Leaving Outdoor Droplets) chamber. The simulations and a comparison with atmospheric observations show that nearly all nucleation throughout the present-day atmosphere involves ammonia or biogenic organic compounds, in addition to sulfuric acid. A considerable fraction of nucleation involves ions, but the relatively weak dependence on ion concentrations indicates that for the processes studied, variations in cosmic ray intensity do not appreciably affect climate through nucleation in the present-day atmosphere. Authors: Eimear M. Dunne, Hamish Gordon, Andreas Kürten, João Almeida, Jonathan Duplissy, Christina Williamson, Ismael K. Ortega, Kirsty J. Pringle, Alexey Adamov, Urs Baltensperger, Peter Barmet, Francois Benduhn, Federico Bianchi, Martin Breitenlechner, Antony Clarke, Joachim Curtius, Josef Dommen, Neil M. Donahue, Sebastian Ehrhart, Richard C. Flagan, Alessandro Franchin, Roberto Guida, Jani Hakala, Armin Hansel, Martin Heinritzi, Tuija Jokinen, Juha Kangasluoma, Jasper Kirkby, Markku Kulmala, Agnieszka Kupc, Michael J. Lawler, Katrianne Lehtipalo, Vladimir Makhmutov, Graham Mann, Serge Mathot, Joonas Merikanto, Pasi Miettinen, Athanasios Nenes, Antti Onnela, Alexandru Rap, Carly L. S. Reddington, Francesco Riccobono, Nigel A. D. Richards, Matti P. Rissanen, Linda Rondo, Nina Sarnela, Siegfried Schobesberger, Kamalika Sengupta, Mario Simon, Mikko Sipilä, James N. Smith, Yuri Stozkhov, Antonio Tomé, Jasmin Tröstl, Paul E. Wagner, Daniela Wimmer, Paul M. Winkler, Douglas R. Worsnop, Kenneth S. Carslaw



[Report] Quantized Faraday and Kerr rotation and axion electrodynamics of a 3D topological insulator

2016-12-02

Topological insulators have been proposed to be best characterized as bulk magnetoelectric materials that show response functions quantized in terms of fundamental physical constants. Here, we lower the chemical potential of three-dimensional (3D) Bi2Se3 films to ~30 meV above the Dirac point and probe their low-energy electrodynamic response in the presence of magnetic fields with high-precision time-domain terahertz polarimetry. For fields higher than 5 tesla, we observed quantized Faraday and Kerr rotations, whereas the dc transport is still semiclassical. A nontrivial Berry’s phase offset to these values gives evidence for axion electrodynamics and the topological magnetoelectric effect. The time structure used in these measurements allows a direct measure of the fine-structure constant based on a topological invariant of a solid-state system. Authors: Liang Wu, M. Salehi, N. Koirala, J. Moon, S. Oh, N. P. Armitage



[Report] Molecular gas in the halo fuels the growth of a massive cluster galaxy at high redshift

2016-12-02

The largest galaxies in the universe reside in galaxy clusters. Using sensitive observations of carbon monoxide, we show that the Spiderweb galaxy—a massive galaxy in a distant protocluster—is forming from a large reservoir of molecular gas. Most of this molecular gas lies between the protocluster galaxies and has low velocity dispersion, indicating that it is part of an enriched intergalactic medium. This may constitute the reservoir of gas that fuels the widespread star formation seen in earlier ultraviolet observations of the Spiderweb galaxy. Our results support the notion that giant galaxies in clusters formed from extended regions of recycled gas at high redshift. Authors: B. H. C. Emonts, M. D. Lehnert, M. Villar-Martín, R. P. Norris, R. D. Ekers, G. A. van Moorsel, H. Dannerbauer, L. Pentericci, G. K. Miley, J. R. Allison, E. M. Sadler, P. Guillard, C. L. Carilli, M. Y. Mao, H. J. A. Röttgering, C. De Breuck, N. Seymour, B. Gullberg, D. Ceverino, P. Jagannathan, J. Vernet, B. T. Indermuehle



[Report] Spectroscopic snapshots of the proton-transfer mechanism in water

2016-12-02

The Grotthuss mechanism explains the anomalously high proton mobility in water as a sequence of proton transfers along a hydrogen-bonded (H-bonded) network. However, the vibrational spectroscopic signatures of this process are masked by the diffuse nature of the key bands in bulk water. Here we report how the much simpler vibrational spectra of cold, composition-selected heavy water clusters, D+(D2O)n, can be exploited to capture clear markers that encode the collective reaction coordinate along the proton-transfer event. By complexing the solvated hydronium “Eigen” cluster [D3O+(D2O)3] with increasingly strong H-bond acceptor molecules (D2, N2, CO, and D2O), we are able to track the frequency of every O-D stretch vibration in the complex as the transferring hydron is incrementally pulled from the central hydronium to a neighboring water molecule. Authors: Conrad T. Wolke, Joseph A. Fournier, Laura C. Dzugan, Matias R. Fagiani, Tuguldur T. Odbadrakh, Harald Knorke, Kenneth D. Jordan, Anne B. McCoy, Knut R. Asmis, Mark A. Johnson



[Report] Reactivation of latent working memories with transcranial magnetic stimulation

2016-12-02

The ability to hold information in working memory is fundamental for cognition. Contrary to the long-standing view that working memory depends on sustained, elevated activity, we present evidence suggesting that humans can hold information in working memory via “activity-silent” synaptic mechanisms. Using multivariate pattern analyses to decode brain activity patterns, we found that the active representation of an item in working memory drops to baseline when attention shifts away. A targeted pulse of transcranial magnetic stimulation produced a brief reemergence of the item in concurrently measured brain activity. This reactivation effect occurred and influenced memory performance only when the item was potentially relevant later in the trial, which suggests that the representation is dynamic and modifiable via cognitive control. The results support a synaptic theory of working memory. Authors: Nathan S. Rose, Joshua J. LaRocque, Adam C. Riggall, Olivia Gosseries, Michael J. Starrett, Emma E. Meyering, Bradley R. Postle



[Report] Selective modulation of cortical state during spatial attention

2016-12-02

Neocortical activity is permeated with endogenously generated fluctuations, but how these dynamics affect goal-directed behavior remains a mystery. We found that ensemble neural activity in primate visual cortex spontaneously fluctuated between phases of vigorous (On) and faint (Off) spiking synchronously across cortical layers. These On-Off dynamics, reflecting global changes in cortical state, were also modulated at a local scale during selective attention. Moreover, the momentary phase of local ensemble activity predicted behavioral performance. Our results show that cortical state is controlled locally within a cortical map according to cognitive demands and reveal the impact of these local changes in cortical state on goal-directed behavior. Authors: Tatiana A. Engel, Nicholas A. Steinmetz, Marc A. Gieselmann, Alexander Thiele, Tirin Moore, Kwabena Boahen



[Report] Gliogenic LTP spreads widely in nociceptive pathways

2016-12-02

Learning and memory formation involve long-term potentiation (LTP) of synaptic strength. A fundamental feature of LTP induction in the brain is the need for coincident pre- and postsynaptic activity. This restricts LTP expression to activated synapses only (homosynaptic LTP) and leads to its input specificity. In the spinal cord, we discovered a fundamentally different form of LTP that is induced by glial cell activation and mediated by diffusible, extracellular messengers, including d-serine and tumor necrosis factor (TNF), and that travel long distances via the cerebrospinal fluid, thereby affecting susceptible synapses at remote sites. The properties of this gliogenic LTP resolve unexplained findings of memory traces in nociceptive pathways and may underlie forms of widespread pain hypersensitivity. Authors: M. T. Kronschläger, R. Drdla-Schutting, M. Gassner, S. D. Honsek, H. L. Teuchmann, J. Sandkühler



[Report] Zika virus produces noncoding RNAs using a multi-pseudoknot structure that confounds a cellular exonuclease

2016-12-02

The outbreak of Zika virus (ZIKV) and associated fetal microcephaly mandates efforts to understand the molecular processes of infection. Related flaviviruses produce noncoding subgenomic flaviviral RNAs (sfRNAs) that are linked to pathogenicity in fetal mice. These viruses make sfRNAs by co-opting a cellular exonuclease via structured RNAs called xrRNAs. We found that ZIKV-infected monkey and human epithelial cells, mouse neurons, and mosquito cells produce sfRNAs. The RNA structure that is responsible for ZIKV sfRNA production forms a complex fold that is likely found in many pathogenic flaviviruses. Mutations that disrupt the structure affect exonuclease resistance in vitro and sfRNA formation during infection. The complete ZIKV xrRNA structure clarifies the mechanism of exonuclease resistance and identifies features that may modulate function in diverse flaviviruses. Authors: Benjamin M. Akiyama, Hannah M. Laurence, Aaron R. Massey, David A. Costantino, Xuping Xie, Yujiao Yang, Pei-Yong Shi, Jay C. Nix, J. David Beckham, Jeffrey S. Kieft



[Report] Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation

2016-12-02

A specialized bone marrow microenvironment (niche) regulates hematopoietic stem cell (HSC) self-renewal and commitment. For successful donor-HSC engraftment, the niche must be emptied via myeloablative irradiation or chemotherapy. However, myeloablation can cause severe complications and even mortality. Here we report that the essential amino acid valine is indispensable for the proliferation and maintenance of HSCs. Both mouse and human HSCs failed to proliferate when cultured in valine-depleted conditions. In mice fed a valine-restricted diet, HSC frequency fell dramatically within 1 week. Furthermore, dietary valine restriction emptied the mouse bone marrow niche and afforded donor-HSC engraftment without chemoirradiative myeloablation. These findings indicate a critical role for valine in HSC maintenance and suggest that dietary valine restriction may reduce iatrogenic complications in HSC transplantation. Authors: Yuki Taya, Yasunori Ota, Adam C. Wilkinson, Ayano Kanazawa, Hiroshi Watarai, Masataka Kasai, Hiromitsu Nakauchi, Satoshi Yamazaki



[Report] Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance

2016-12-02

A single hematopoietic stem cell (HSC) is capable of reconstituting hematopoiesis and maintaining homeostasis by balancing self-renewal and cell differentiation. The mechanisms of HSC division balance, however, are not yet defined. Here we demonstrate, by characterizing at the single-cell level a purified and minimally heterogeneous murine Tie2+ HSC population, that these top hierarchical HSCs preferentially undergo symmetric divisions. The induction of mitophagy, a quality control process in mitochondria, plays an essential role in self-renewing expansion of Tie2+ HSCs. Activation of the PPAR (peroxisome proliferator–activated receptor)–fatty acid oxidation pathway promotes expansion of Tie2+ HSCs through enhanced Parkin recruitment in mitochondria. These metabolic pathways are conserved in human TIE2+ HSCs. Our data thus identify mitophagy as a key mechanism of HSC expansion and suggest potential methods of cell-fate manipulation through metabolic pathways. Authors: Kyoko Ito, Raphaël Turcotte, Jinhua Cui, Samuel E. Zimmerman, Sandra Pinho, Toshihide Mizoguchi, Fumio Arai, Judith M. Runnels, Clemens Alt, Julie Teruya-Feldstein, Jessica C. Mar, Rajat Singh, Toshio Suda, Charles P. Lin, Paul S. Frenette, Keisuke Ito



[Report] Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade

2016-12-02

Blocking Programmed Death–1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies. Authors: Kristen E. Pauken, Morgan A. Sammons, Pamela M. Odorizzi, Sasikanth Manne, Jernej Godec, Omar Khan, Adam M. Drake, Zeyu Chen, Debattama R. Sen, Makoto Kurachi, R. Anthony Barnitz, Caroline Bartman, Bertram Bengsch, Alexander C. Huang, Jason M. Schenkel, Golnaz Vahedi, W. Nicholas Haining, Shelley L. Berger, E. John Wherry



[Report] The epigenetic landscape of T cell exhaustion

2016-12-02

Exhausted T cells in cancer and chronic viral infection express distinctive patterns of genes, including sustained expression of programmed cell death protein 1 (PD-1). However, the regulation of gene expression in exhausted T cells is poorly understood. Here, we define the accessible chromatin landscape in exhausted CD8+ T cells and show that it is distinct from functional memory CD8+ T cells. Exhausted CD8+ T cells in humans and a mouse model of chronic viral infection acquire a state-specific epigenetic landscape organized into functional modules of enhancers. Genome editing shows that PD-1 expression is regulated in part by an exhaustion-specific enhancer that contains essential RAR, T-bet, and Sox3 motifs. Functional enhancer maps may offer targets for genome editing that alter gene expression preferentially in exhausted CD8+ T cells. Authors: Debattama R. Sen, James Kaminski, R. Anthony Barnitz, Makoto Kurachi, Ulrike Gerdemann, Kathleen B. Yates, Hsiao-Wei Tsao, Jernej Godec, Martin W. LaFleur, Flavian D. Brown, Pierre Tonnerre, Raymond T. Chung, Damien C. Tully, Todd M. Allen, Nicole Frahm, Georg M. Lauer, E. John Wherry, Nir Yosef, W. Nicholas Haining



[Report] Generation of influenza A viruses as live but replication-incompetent virus vaccines

2016-12-02

The conversion of life-threatening viruses into live but avirulent vaccines represents a revolution in vaccinology. In a proof-of-principle study, we expanded the genetic code of the genome of influenza A virus via a transgenic cell line containing orthogonal translation machinery. This generated premature termination codon (PTC)–harboring viruses that exerted full infectivity but were replication-incompetent in conventional cells. Genome-wide optimization of the sites for incorporation of multiple PTCs resulted in highly reproductive and genetically stable progeny viruses in transgenic cells. In mouse, ferret, and guinea pig models, vaccination with PTC viruses elicited robust humoral, mucosal, and T cell–mediated immunity against antigenically distinct influenza viruses and even neutralized existing infecting strains. The methods presented here may become a general approach for generating live virus vaccines that can be adapted to almost any virus. Authors: Longlong Si, Huan Xu, Xueying Zhou, Ziwei Zhang, Zhenyu Tian, Yan Wang, Yiming Wu, Bo Zhang, Zhenlan Niu, Chuanling Zhang, Ge Fu, Sulong Xiao, Qing Xia, Lihe Zhang, Demin Zhou



[New Products] New Products

2016-12-02

A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.



[Business Office Feature] Webinar | Characterizing the maternal immune environment during pregnancy: Implications for autism spectrum disorders

2016-12-02

Under normal conditions, the maternal immune system is uniquely regulated during pregnancy to maintain a pathogen-free, yet noninflammatory environment for the developing fetus. However, factors such as cytokines and chemokines produced during gestation can have developmental consequences for the fetus. In particular, maternal immune dysregulation during pregnancy has been frequently associated with increased risk of autism spectrum disorders. This webinar will discuss the relationship between the maternal immune environment and autism risk, highlighting findings from the largest population-based prospective study to date to have examined the relationship between mid-gestational maternal cytokines and chemokines and risk for autism.View the Webinar Authors: Karen Jones, Anthony Saporita



[Working Life] Making a difference, differently

2016-12-02

Author: Matthew Tuthill