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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: 2017-03-23T13:55:15-04:00

 



[Research Article] Self-assembly of genetically encoded DNA-protein hybrid nanoscale shapes

2017-03-24

We describe an approach to bottom-up fabrication that allows integration of the functional diversity of proteins into designed three-dimensional structural frameworks. A set of custom staple proteins based on transcription activator–like effector proteins folds a double-stranded DNA template into a user-defined shape. Each staple protein is designed to recognize and closely link two distinct double-helical DNA sequences at separate positions on the template. We present design rules for constructing megadalton-scale DNA-protein hybrid shapes; introduce various structural motifs, such as custom curvature, corners, and vertices; and describe principles for creating multilayer DNA-protein objects with enhanced rigidity. We demonstrate self-assembly of our hybrid nanostructures in one-pot mixtures that include the genetic information for the designed proteins, the template DNA, RNA polymerase, ribosomes, and cofactors for transcription and translation. Authors: Florian Praetorius, Hendrik Dietz



[Review] Vertically extensive and unstable magmatic systems: A unified view of igneous processes

2017-03-24

Volcanoes are an expression of their underlying magmatic systems. Over the past three decades, the classical focus on upper crustal magma chambers has expanded to consider magmatic processes throughout the crust. A transcrustal perspective must balance slow (plate tectonic) rates of melt generation and segregation in the lower crust with new evidence for rapid melt accumulation in the upper crust before many volcanic eruptions. Reconciling these observations is engendering active debate about the physical state, spatial distribution, and longevity of melt in the crust. Here we review evidence for transcrustal magmatic systems and highlight physical processes that might affect the growth and stability of melt-rich layers, focusing particularly on conditions that cause them to destabilize, ascend, and accumulate in voluminous but ephemeral shallow magma chambers. Authors: Katharine V. Cashman, R. Stephen J. Sparks, Jonathan D. Blundy



[Research Article] Dynamics of cortical dendritic membrane potential and spikes in freely behaving rats

2017-03-24

Neural activity in vivo is primarily measured using extracellular somatic spikes, which provide limited information about neural computation. Hence, it is necessary to record from neuronal dendrites, which can generate dendritic action potentials (DAPs) in vitro, which can profoundly influence neural computation and plasticity. We measured neocortical sub- and suprathreshold dendritic membrane potential (DMP) from putative distal-most dendrites using tetrodes in freely behaving rats over multiple days with a high degree of stability and submillisecond temporal resolution. DAP firing rates were several-fold larger than somatic rates. DAP rates were also modulated by subthreshold DMP fluctuations, which were far larger than DAP amplitude, indicating hybrid, analog-digital coding in the dendrites. Parietal DAP and DMP exhibited egocentric spatial maps comparable to pyramidal neurons. These results have important implications for neural coding and plasticity. Authors: Jason J. Moore, Pascal M. Ravassard, David Ho, Lavanya Acharya, Ashley L. Kees, Cliff Vuong, Mayank R. Mehta



[Research Article] Transition from turbulent to coherent flows in confined three-dimensional active fluids

2017-03-24

Transport of fluid through a pipe is essential for the operation of macroscale machines and microfluidic devices. Conventional fluids only flow in response to external pressure. We demonstrate that an active isotropic fluid, composed of microtubules and molecular motors, autonomously flows through meter-long three-dimensional channels. We establish control over the magnitude, velocity profile, and direction of the self-organized flows and correlate these to the structure of the extensile microtubule bundles. The inherently three-dimensional transition from bulk-turbulent to confined-coherent flows occurs concomitantly with a transition in the bundle orientational order near the surface and is controlled by a scale-invariant criterion related to the channel profile. The nonequilibrium transition of confined isotropic active fluids can be used to engineer self-organized soft machines. Authors: Kun-Ta Wu, Jean Bernard Hishamunda, Daniel T. N. Chen, Stephen J. DeCamp, Ya-Wen Chang, Alberto Fernández-Nieves, Seth Fraden, Zvonimir Dogic



[Research Article] Cryo-EM structures of the triheteromeric NMDA receptor and its allosteric modulation

2017-03-24

N-methyl-d-aspartate receptors (NMDARs) are heterotetrameric ion channels assembled as diheteromeric or triheteromeric complexes. Here, we report structures of the triheteromeric GluN1/GluN2A/GluN2B receptor in the absence or presence of the GluN2B-specific allosteric modulator Ro 25-6981 (Ro), determined by cryogenic electron microscopy (cryo-EM). In the absence of Ro, the GluN2A and GluN2B amino-terminal domains (ATDs) adopt “closed” and “open” clefts, respectively. Upon binding Ro, the GluN2B ATD clamshell transitions from an open to a closed conformation. Consistent with a predominance of the GluN2A subunit in ion channel gating, the GluN2A subunit interacts more extensively with GluN1 subunits throughout the receptor, in comparison with the GluN2B subunit. Differences in the conformation of the pseudo-2-fold–related GluN1 subunits further reflect receptor asymmetry. The triheteromeric NMDAR structures provide the first view of the most common NMDA receptor assembly and show how incorporation of two different GluN2 subunits modifies receptor symmetry and subunit interactions, allowing each subunit to uniquely influence receptor structure and function, thus increasing receptor complexity. Authors: Wei Lü, Juan Du, April Goehring, Eric Gouaux



[Editorial] UK science, post-Brexit

2017-03-24

Nine months since the British vote to exit the European Union (“Brexit”), the UK science community's initial dismay has given way to hard-boiled determination to limit the damage it will do to universities and research. On 29 March, Prime Minister Theresa May is expected to give formal notification of the UK's intention to withdraw under Article 50 of the Lisbon Treaty, the constitutional basis of the EU. This will set in motion a 2-year period of intense negotiation on the terms of the UK's divorce, and any future agreements with the EU—with research just one line item on a long list of issues to be resolved. Author: James Wilsdon



[In Brief] News at a glance

2017-03-24

In science news around the world, the San people of Southern Africa release a code of ethics to guide researchers wanting to study their culture or genes, a series of films documenting nuclear tests from the 1945 to 1962 is released on YouTube, U.K. regulators grant the first license for mitochondrial replacement therapy, a researcher is accused of putting his name to a paper partially ghost-written by employees at chemical giant Monsanto, and more. Also, the administration of U.S. President Donald Trump will reopen a review of a 2012 fuel efficiency agreement by automakers that would double efficiency by 2025. And the Trump administration also plans to rescind an Obama-era rule requiring public disclosure of the chemicals used in fracking on public lands.



[In Depth] Trump's 2018 budget proposal ‘devalues’ science

2017-03-24

The 2018 budget proposal that President Donald Trump unveiled last week confirms two things that U.S. scientists have long suspected: The new president is no fan of research, and his administration has no overarching strategy for funding science. Deep proposed cuts to research at several agencies offer evidence that Trump doesn't see science—of any kind—as a spending priority. And along with neglect there's indifference. There's no telling how the National Science Foundation would fare, for example, because the budget blueprint doesn't mention it. In the meantime, scientists are also worried about the fate of this year's research budgets after Trump proposed cuts to the category that funds all civilian research. More angst: There's no word yet on whether the president will even appoint a science adviser, much less when he will fill dozens of senior slots at research agencies. Author: Jeffrey Mervis



[In Depth] Can flu shots help women get pregnant?

2017-03-24

Two new clinical trials are testing whether flu vaccines increase the effectiveness of in vitro fertilization (IVF). The studies draw on new discoveries about the immune system's role in reproduction. Doctors used to think that the immune system had to shut down during pregnancy so that it wouldn't destroy the embryo. Now, researchers realize that the immune system remains active but learns to accept the embryo, developing what's known as tolerance. The trials will test whether flu shots increase tolerance toward the embryo and improve the success rate of IVF. One trial includes women undergoing IVF with embryos created from their own eggs, and the other trial includes women who receive embryos created from donor eggs.  Author: Mitch Leslie



[In Depth] Ma, where did they put T. rex?

2017-03-24

A new study gives the long-standing dinosaur family tree an overhaul. Based on analyses of hundreds of traits gleaned from existing studies and fossils, the study strikes down a fundamental split of dinosaurs into "bird-hipped" and "reptile-hipped"; it also shifts the charismatic theropods—the group that includes Tyrannosaurus rex and eventually gave rise to birds—to a new spot on the tree, closer to the bird-hipped dinos. The reorganization of the tree suggests that hypercarnivory evolved in different groups through convergent evolution, and may upend the picture of where dinosaurs arose. But don't throw out your dog-eared dino books just yet, other researchers caution: This new family tree is likely to be debated for some time to come. Author: Carolyn Gramling



[In Depth] New Zealand temblor points to threat of compound quakes

2017-03-24

A reassuring rule of thumb about earthquakes is breaking down. For decades, seismologists had assumed that individual faults—as well as isolated segments of longer faults—rupture independently of one another. That limits the maximum size of the potential earthquake that a fault zone can generate. But the magnitude-7.8 earthquake that struck New Zealand just after midnight on 14 November 2016—among the largest in the islands' modern history—has reduced that thinking to rubble. According to a new study, published online this week in Science, the heavy shaking in the Kaikoura quake was amassed by ruptures on at least 12 different faults, in some cases so far apart that they were thought to be immune to each other's influence. Author: Betsy Mason



[In Depth] In search for unseen matter, physicists turn to dark sector

2017-03-24

Scientists hunting unseen dark matter are looking deeper into the shadows. With searches for a favored dark matter candidate—weakly interacting massive particles (WIMPs)—coming up empty, physicists are now turning to the hypothetical "dark sector": an entire shadow realm of hidden particles. This week, physicists will meet at the University of Maryland in College Park for a workshop, sponsored by the U.S. Department of Energy (DOE), to mull ideas for a possible $10 million short-term experiment that would complement the agency's current WIMP search and other dark-matter efforts. And many researchers believe DOE should focus on the dark sector. Whereas WIMPs would be a single massive particle tacked onto the standard model of known particles, the dark sector would consist of a slew of lighter particles and forces—such as a dark version of electromagnetism—with tenuous connections to known particles. To spot dark-sector particles, physicists will have to rethink their detection techniques, but the new experiment could be small and cheap, physicists say. Still, DOE officials warn that the $10 million isn't a sure thing. Author: Adrian Cho



[In Depth] Tweak makes U.S. nukes more precise—and deadlier

2017-03-24

A small fix made in the name of "stockpile stewardship" is turning U.S. submarine–launched missiles into more precise weapons. An improved mechanism installed in aging warhead now makes it possible to adjust the height at which they detonate, according to three experts writing in The Bulletin of the Atomic Scientists. This vastly increases the weapons' efficiency, the experts say, creating the impression that submarine-launched weapons could be used in a first strike against Russia's fixed missile silos. About 500 such warheads have been deployed on submarines; more than 1000 updated warheads are in production. The innovation could create "a deeply destabilizing and dangerous strategic nuclear situation," the authors warn. Author: Eliot Marshall



[Feature] Fishy business

2017-03-24

Two Swedish fish researchers, with the aid of five colleagues elsewhere in the world, have alleged fraud in a study on the effects of microplastics on larval fish published in Science by two scientists at Uppsala University (UU) in June 2016. The study supposedly took place at the Ar Research Station in Gotland, but the whistleblowers say it never happened, based on eyewitness testimony and other evidence. A preliminary investigation by UU dismissed the claims in August 2016; a second investigation, by an expert panel at Sweden's Central Ethical Review Board, is still ongoing. An expert hired by that panel filed a more damning report last February that raised the possibility of fraud. Now, both sides are awaiting the expert panel's final verdict, which may influence an ongoing debate about how Swedish institutions investigate research misconduct. Author: Martin Enserink



[Perspective] Macrophage, a long-distance middleman

2017-03-24

Macrophages were first identified in transparent starfish larvae (Astropecten pentacanthus) more than a century ago, so it is fitting that a new function for macrophages would again be discovered in transparent marine larvae, this time from zebra fish (Danio rerio). On page 1317 of this issue, Eom and Parichy (1) reveal a wholly unexpected tissue-specific function of macrophages—their cardinal role in long-distance communication between nonimmune cells. In doing so, macrophages choreograph the patterning of pigment cells that eventually form the stripes on zebrafish. Author: Martin Guilliams



[Perspective] Powering up perovskite photoresponse

2017-03-24

The most notable scientific milestone in photovoltaics in the past several years is the emergence of solar cells based on hybrid organic-inorganic perovskite materials. While conventional silicon and thin-film solar cells have seen steady improvements in their power-conversion efficiencies (PCEs) spanning several decades, hybrid perovskite solar cells have already reached a certified 22.1% PCE (1), matching conventional solar cell technologies in only a few years since their first device architecture was tested. Setting the stage for a disruptive technology in the field of photovoltaics is the seemingly winning combination of properties of hybrid perovskite materials: high absorption coefficient and a tunable energy band gap in wavelengths ideal for solar cells; long diffusion lengths and lifetimes for photogenerated charge carriers, which easily dissociate into efficiently collected electrons and holes; Earth-abundant elemental composition; and their compatibility with low-cost and low-temperature fabrication methods (2–5). On page 1288 of this issue, Blancon et al. (6) report on the observation of an enhanced photoresponse for layered perovskite materials. The results add, literally, a new dimension to the further development of high-performance perovskite solar cells. Authors: Osman M. Bakr, Omar F. Mohammed



[Perspective] Bringing proteins into the fold

2017-03-24

Molecular engineers have become increasingly adept at repurposing life's building blocks to make custom self-assembled shapes. Because a single drop of solution contains billions of such shapes, DNA origami smiley faces (1), RNA stars (2), and designer protein polyhedra (3) may vastly outnumber most other human-made objects on Earth. These shapes lack immediate practical utility, but they transmit a powerful message: Researchers are beginning to understand how molecules self-assemble. On page 1283 of this issue, Praetorius and Dietz make another leap forward by demonstrating a novel class of nanostructures, namely DNA-protein hybrid shapes (4). This is an important advance because it provides a method to create human-designed shapes out of ingredients that are generally compatible with living systems. Author: Shawn M. Douglas



[Perspective] From chaos to order in active fluids

2017-03-24

There are few sights more spectacular than the swarming of a school of fish or a flock of birds that suddenly gives way to a directional motion. Arguably, our admiration is rooted in the surprise that individual organisms, capable of self-propulsion on their own, organize to move en masse in a coherent fashion. Coherent motion is common in a large class of biological and synthetic materials that are often referred to as active matter. Such materials consist of particles immersed in a fluid that can extract energy from their surroundings (or internal fuel) and convert it into directed motion. Living organisms, biological tissues, rods on a vibrated plate, and self-phoretic colloids are just a few examples (1). Similar to schools of fish and flocks of birds, active matter often exhibits random swarming motion (2–5) that until now was impossible to control or use. On page 1284 of this issue, Wu et al. (6) demonstrate that an active fluid can be manipulated to flow in a particular direction without any external stimuli by confining it in microchannels. Author: Alexander Morozov



[Perspective] Using fire to promote biodiversity

2017-03-24

Fire profoundly influences people, climate, and ecosystems (1). The impacts of this interaction are likely to grow, with climate models forecasting widespread increases in fire frequency and intensity because of rising global temperatures (2). However, the relationship between fire and biodiversity is complex (3, 4). Many plants and animals require fire for their survival, yet even in fire-prone ecosystems, some species and communities are highly sensitive to fire. Recent studies (2, 3, 5, 6) are helping to define fire regimes that support the conservation of species with different requirements in a rapidly changing world. Authors: L. T. Kelly, L. Brotons



[Perspective] Genes, environment, and “bad luck”

2017-03-24

It is a human trait to search for explanations for catastrophic events and rule out mere “chance” or “bad luck.” When it comes to human cancer, the issue of natural causes versus bad luck was raised by Tomasetti and Vogelstein about 2 years ago (1). Their study, which was widely misinterpreted as saying that most cancers are due neither to genetic inheritance nor environmental factors but simply bad luck, sparked controversy. To date, a few hundred papers have been written in response, including (2–6), with some [e.g., (2)] coming to opposite conclusions. What is this controversy about? Tomasetti and Vogelstein concluded that 65% of the differences in the risk of certain cancers is linked to stem cell divisions in the various cancerous tissues examined (1). On page 1330 of this issue, Tomasetti et al. (7) provide further evidence that this is not specific to the United States. Authors: Martin A. Nowak, Bartlomiej Waclaw



[Retrospective] Hans Rosling (1948–2017)

2017-03-24

Like a lot of Hans Rosling's admirers, we discovered his work via his famous 2006 TED talk, “The Best Stats You've Ever Seen.” It was a mind-blowing speech (with more than 11 million views to date) with innovative graphics, good jokes, and a profound message: The world is getting better, and even some of the poorest countries are making progress. Hans was a showman, but he didn't sacrifice an ounce of complexity. He was—and this is a term of honor in our house—a data nerd. We sang his praises to just about anyone who would listen. Authors: Bill Gates, Melinda Gates



[Policy Forum] A roadmap for rapid decarbonization

2017-03-24

Although the Paris Agreement's goals (1) are aligned with science (2) and can, in principle, be technically and economically achieved (3), alarming inconsistencies remain between science-based targets and national commitments. Despite progress during the 2016 Marrakech climate negotiations, long-term goals can be trumped by political short-termism. Following the Agreement, which became international law earlier than expected, several countries published mid-century decarbonization strategies, with more due soon. Model-based decarbonization assessments (4) and scenarios often struggle to capture transformative change and the dynamics associated with it: disruption, innovation, and nonlinear change in human behavior. For example, in just 2 years, China's coal use swung from 3.7% growth in 2013 to a decline of 3.7% in 2015 (5). To harness these dynamics and to calibrate for short-term realpolitik, we propose framing the decarbonization challenge in terms of a global decadal roadmap based on a simple heuristic—a “carbon law”—of halving gross anthropogenic carbon-dioxide (CO2) emissions every decade. Complemented by immediately instigated, scalable carbon removal and efforts to ramp down land-use CO2 emissions, this can lead to net-zero emissions around mid-century, a path necessary to limit warming to well below 2°C. Authors: Johan Rockström, Owen Gaffney, Joeri Rogelj, Malte Meinshausen, Nebojsa Nakicenovic, Hans Joachim Schellnhuber



[Book Review] Rain check

2017-03-24

Make It Rain, Kristine Harper's detailed history of weather control in the United States, includes colorful details of cloud-seeding experiments, but the book is not so much about attempts to control the weather as it is about the political battles waged over the harnessing of the atmosphere: the control of weather control itself. Rather than revealing a history of what we might today call evidence-led policy, the book is a rogue's gallery of policy-led evidence, offering lessons about how science can be used as a tool of the state. Author: Sarah Dry



[Letter] Patent pools for CRISPR technology

2017-03-24

Author: Lawrence Horn



[Letter] Patent pools for CRISPR technology—Response

2017-03-24

Authors: Jorge L. Contreras, Jacob S. Sherkow



[Letter] Specimen collection crucial to taxonomy

2017-03-24

Authors: Eliécer E. Gutiérrez, Ronald H. Pine












[This Week in Science] Metal-oxide synergy

2017-03-24

Author: Phil Szuromi












[This Week in Science] Why pain and stress lead to depression

2017-03-24

Author: Leslie K. Ferrarelli



[This Week in Science] Cancer and the unavoidable R factor

2017-03-24

Author: Paula A. Kiberstis



[This Week in Science] Making magma chambers from mush

2017-03-24

Author: Brent Grocholski












[This Week in Science] Go with the changing flow

2017-03-24

Author: Marc S. Lavine


















[This Week in Science] Fire management, made to measure

2017-03-24

Author: Julia Fahrenkamp-Uppenbrink






[This Week in Science] It's easier to see green

2017-03-24

Author: Shahid Naeem



[Editors' Choice] A new angle on streams

2017-03-24

Author: H. Jesse Smith



[Editors' Choice] Turning toys into tools

2017-03-24

Author: Megan Eldred












[Editors' Choice] Notch1 promotes cancer spread

2017-03-24

Author: Priscilla N. Kelly



[Editors' Choice] Dirac cones in a boron monolayer

2017-03-24

Author: Jelena Stajic



[Report] [C ii] 158-μm emission from the host galaxies of damped Lyman-alpha systems

2017-03-24

Gas surrounding high-redshift galaxies has been studied through observations of absorption line systems toward background quasars for decades. However, it has proven difficult to identify and characterize the galaxies associated with these absorbers due to the intrinsic faintness of the galaxies compared with the quasars at optical wavelengths. Using the Atacama Large Millimeter/Submillimeter Array, we report on detections of [C ii] 158-μm line and dust-continuum emission from two galaxies associated with two such absorbers at a redshift of z ~ 4. Our results indicate that the hosts of these high-metallicity absorbers have physical properties similar to massive star-forming galaxies and are embedded in enriched neutral hydrogen gas reservoirs that extend well beyond the star-forming interstellar medium of these galaxies. Authors: Marcel Neeleman, Nissim Kanekar, J. Xavier Prochaska, Marc Rafelski, Chris L. Carilli, Arthur M. Wolfe



[Report] Extremely efficient internal exciton dissociation through edge states in layered 2D perovskites

2017-03-24

Understanding and controlling charge and energy flow in state-of-the-art semiconductor quantum wells has enabled high-efficiency optoelectronic devices. Two-dimensional (2D) Ruddlesden-Popper perovskites are solution-processed quantum wells wherein the band gap can be tuned by varying the perovskite-layer thickness, which modulates the effective electron-hole confinement. We report that, counterintuitive to classical quantum-confined systems where photogenerated electrons and holes are strongly bound by Coulomb interactions or excitons, the photophysics of thin films made of Ruddlesden-Popper perovskites with a thickness exceeding two perovskite-crystal units (>1.3 nanometers) is dominated by lower-energy states associated with the local intrinsic electronic structure of the edges of the perovskite layers. These states provide a direct pathway for dissociating excitons into longer-lived free carriers that substantially improve the performance of optoelectronic devices. Authors: J.-C. Blancon, H. Tsai, W. Nie, C. C. Stoumpos, L. Pedesseau, C. Katan, M. Kepenekian, C. M. M. Soe, K. Appavoo, M. Y. Sfeir, S. Tretiak, P. M. Ajayan, M. G. Kanatzidis, J. Even, J. J. Crochet, A. D. Mohite



[Report] Grain boundary stability governs hardening and softening in extremely fine nanograined metals

2017-03-24

Conventional metals become harder with decreasing grain sizes, following the classical Hall-Petch relationship. However, this relationship fails and softening occurs at some grain sizes in the nanometer regime for some alloys. In this study, we discovered that plastic deformation mechanism of extremely fine nanograined metals and their hardness are adjustable through tailoring grain boundary (GB) stability. The electrodeposited nanograined nickel-molybdenum (Ni–Mo) samples become softened for grain sizes below 10 nanometers because of GB-mediated processes. With GB stabilization through relaxation and Mo segregation, ultrahigh hardness is achieved in the nanograined samples with a plastic deformation mechanism dominated by generation of extended partial dislocations. Grain boundary stability provides an alternative dimension, in addition to grain size, for producing novel nanograined metals with extraordinary properties. Authors: J. Hu, Y. N. Shi, X. Sauvage, G. Sha, K. Lu



[Report] Active sites for CO2 hydrogenation to methanol on Cu/ZnO catalysts

2017-03-24

The active sites over commercial copper/zinc oxide/aluminum oxide (Cu/ZnO/Al2O3) catalysts for carbon dioxide (CO2) hydrogenation to methanol, the Zn-Cu bimetallic sites or ZnO-Cu interfacial sites, have recently been the subject of intense debate. We report a direct comparison between the activity of ZnCu and ZnO/Cu model catalysts for methanol synthesis. By combining x-ray photoemission spectroscopy, density functional theory, and kinetic Monte Carlo simulations, we can identify and characterize the reactivity of each catalyst. Both experimental and theoretical results agree that ZnCu undergoes surface oxidation under the reaction conditions so that surface Zn transforms into ZnO and allows ZnCu to reach the activity of ZnO/Cu with the same Zn coverage. Our results highlight a synergy of Cu and ZnO at the interface that facilitates methanol synthesis via formate intermediates. Authors: Shyam Kattel, Pedro J. Ramírez, Jingguang G. Chen, José A. Rodriguez, Ping Liu



[Report] How “you” makes meaning

2017-03-24

“You” is one of the most common words in the English language. Although it typically refers to the person addressed (“How are you?”), “you” is also used to make timeless statements about people in general (“You win some, you lose some.”). Here, we demonstrate that this ubiquitous but understudied linguistic device, known as “generic-you,” has important implications for how people derive meaning from experience. Across six experiments, we found that generic-you is used to express norms in both ordinary and emotional contexts and that producing generic-you when reflecting on negative experiences allows people to “normalize” their experience by extending it beyond the self. In this way, a simple linguistic device serves a powerful meaning-making function. Authors: Ariana Orvell, Ethan Kross, Susan A. Gelman



[Report] Dengue diversity across spatial and temporal scales: Local structure and the effect of host population size

2017-03-24

A fundamental mystery for dengue and other infectious pathogens is how observed patterns of cases relate to actual chains of individual transmission events. These pathways are intimately tied to the mechanisms by which strains interact and compete across spatial scales. Phylogeographic methods have been used to characterize pathogen dispersal at global and regional scales but have yielded few insights into the local spatiotemporal structure of endemic transmission. Using geolocated genotype (800 cases) and serotype (17,291 cases) data, we show that in Bangkok, Thailand, 60% of dengue cases living <200 meters apart come from the same transmission chain, as opposed to 3% of cases separated by 1 to 5 kilometers. At distances <200 meters from a case (encompassing an average of 1300 people in Bangkok), the effective number of chains is 1.7. This number rises by a factor of 7 for each 10-fold increase in the population of the “enclosed” region. This trend is observed regardless of whether population density or area increases, though increases in density over 7000 people per square kilometer do not lead to additional chains. Within Thailand these chains quickly mix, and by the next dengue season viral lineages are no longer highly spatially structured within the country. In contrast, viral flow to neighboring countries is limited. These findings are consistent with local, density-dependent transmission and implicate densely populated communities as key sources of viral diversity, with home location the focal point of transmission. These findings have important implications for targeted vector control and active surveillance. Authors: Henrik Salje, Justin Lessler, Irina Maljkovic Berry, Melanie C. Melendrez, Timothy Endy, Siripen Kalayanarooj, Atchareeya A-Nuegoonpipat, Sumalee Chanama, Somchai Sangkijporn, Chonticha Klungthong, Butsaya Thaisomboonsuk, Ananda Nisalak, Robert V. Gibbons, Sopon Iamsirithaworn, Louis R. Macareo, In-Kyu Yoon, Areerat Sangarsang, Richard G. Jarman, Derek A. T. Cummings



[Report] Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex

2017-03-24

The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that becomes activated at the lysosome in response to nutrient cues. Here, we identify cholesterol, an essential building block for cellular growth, as a nutrient input that drives mTORC1 recruitment and activation at the lysosomal surface. The lysosomal transmembrane protein, SLC38A9, is required for mTORC1 activation by cholesterol through conserved cholesterol-responsive motifs. Moreover, SLC38A9 enables mTORC1 activation by cholesterol independently from its arginine-sensing function. Conversely, the Niemann-Pick C1 (NPC1) protein, which regulates cholesterol export from the lysosome, binds to SLC38A9 and inhibits mTORC1 signaling through its sterol transport function. Thus, lysosomal cholesterol drives mTORC1 activation and growth signaling through the SLC38A9-NPC1 complex. Authors: Brian M. Castellano, Ashley M. Thelen, Ofer Moldavski, McKenna Feltes, Reini E. N. van der Welle, Laurel Mydock-McGrane, Xuntian Jiang, Robert J van Eijkeren, Oliver B. Davis, Sharon M. Louie, Rushika M. Perera, Douglas F. Covey, Daniel K. Nomura, Daniel S. Ory, Roberto Zoncu



[Report] A conserved NAD+ binding pocket that regulates protein-protein interactions during aging

2017-03-24

DNA repair is essential for life, yet its efficiency declines with age for reasons that are unclear. Numerous proteins possess Nudix homology domains (NHDs) that have no known function. We show that NHDs are NAD+ (oxidized form of nicotinamide adenine dinucleotide) binding domains that regulate protein-protein interactions. The binding of NAD+ to the NHD domain of DBC1 (deleted in breast cancer 1) prevents it from inhibiting PARP1 [poly(adenosine diphosphate–ribose) polymerase], a critical DNA repair protein. As mice age and NAD+ concentrations decline, DBC1 is increasingly bound to PARP1, causing DNA damage to accumulate, a process rapidly reversed by restoring the abundance of NAD+. Thus, NAD+ directly regulates protein-protein interactions, the modulation of which may protect against cancer, radiation, and aging. Authors: Jun Li, Michael S. Bonkowski, Sébastien Moniot, Dapeng Zhang, Basil P. Hubbard, Alvin J. Y. Ling, Luis A. Rajman, Bo Qin, Zhenkun Lou, Vera Gorbunova, L. Aravind, Clemens Steegborn, David A. Sinclair



[Report] A macrophage relay for long-distance signaling during postembryonic tissue remodeling

2017-03-24

Macrophages have diverse functions in immunity as well as in development and homeostasis. We identified a function for these cells in long-distance communication during postembryonic tissue remodeling. Ablation of macrophages in zebrafish prevented melanophores from coalescing into adult pigment stripes. Melanophore organization depends on signals provided by cells of the yellow xanthophore lineage via airinemes, long filamentous projections with vesicles at their tips. We show that airineme extension from originating cells, as well as vesicle deposition on target cells, depend on interactions with macrophages. These findings identify a role for macrophages in relaying long-range signals between nonimmune cells. This signaling modality may function in the remodeling and homeostasis of other tissues during normal development and disease. Authors: Dae Seok Eom, David M. Parichy



[Report] Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity

2017-03-24

Notch receptor activation initiates cell fate decisions and is distinctive in its reliance on mechanical force and protein glycosylation. The 2.5-angstrom-resolution crystal structure of the extracellular interacting region of Notch1 complexed with an engineered, high-affinity variant of Jagged1 (Jag1) reveals a binding interface that extends ~120 angstroms along five consecutive domains of each protein. O-Linked fucose modifications on Notch1 epidermal growth factor–like (EGF) domains 8 and 12 engage the EGF3 and C2 domains of Jag1, respectively, and different Notch1 domains are favored in binding to Jag1 than those that bind to the Delta-like 4 ligand. Jag1 undergoes conformational changes upon Notch binding, exhibiting catch bond behavior that prolongs interactions in the range of forces required for Notch activation. This mechanism enables cellular forces to regulate binding, discriminate among Notch ligands, and potentiate Notch signaling. Authors: Vincent C. Luca, Byoung Choul Kim, Chenghao Ge, Shinako Kakuda, Di Wu, Mehdi Roein-Peikar, Robert S. Haltiwanger, Cheng Zhu, Taekjip Ha, K. Christopher Garcia



[Report] PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D

2017-03-24

Activating mutations in PIK3CA, the gene encoding phosphoinositide-(3)-kinase α (PI3Kα), are frequently found in estrogen receptor (ER)–positive breast cancer. PI3Kα inhibitors, now in late-stage clinical development, elicit a robust compensatory increase in ER-dependent transcription that limits therapeutic efficacy. We investigated the chromatin-based mechanisms leading to the activation of ER upon PI3Kα inhibition. We found that PI3Kα inhibition mediates an open chromatin state at the ER target loci in breast cancer models and clinical samples. KMT2D, a histone H3 lysine 4 methyltransferase, is required for FOXA1, PBX1, and ER recruitment and activation. AKT binds and phosphorylates KMT2D, attenuating methyltransferase activity and ER function, whereas PI3Kα inhibition enhances KMT2D activity. These findings uncover a mechanism that controls the activation of ER by the posttranslational modification of epigenetic regulators, providing a rationale for epigenetic therapy in ER-positive breast cancer. Authors: Eneda Toska, Hatice U. Osmanbeyoglu, Pau Castel, Carmen Chan, Ronald C. Hendrickson, Moshe Elkabets, Maura N. Dickler, Maurizio Scaltriti, Christina S. Leslie, Scott A. Armstrong, José Baselga



[Report] Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention

2017-03-24

Cancers are caused by mutations that may be inherited, induced by environmental factors, or result from DNA replication errors (R). We studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries throughout the world. The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. The major role of R mutations in cancer etiology was supported by an independent approach, based solely on cancer genome sequencing and epidemiological data, which suggested that R mutations are responsible for two-thirds of the mutations in human cancers. All of these results are consistent with epidemiological estimates of the fraction of cancers that can be prevented by changes in the environment. Moreover, they accentuate the importance of early detection and intervention to reduce deaths from the many cancers arising from unavoidable R mutations. Authors: Cristian Tomasetti, Lu Li, Bert Vogelstein



[New Products] New Products

2017-03-24

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



[Working Life] Learning from rejections

2017-03-24

Author: Andy Tay