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   ISSN (Print) 0036-8075 - ISSN (Online) 1095-9203
   Published by AAAS Homepage  [6 journals]
  • [Research Article] An adipo-biliary-uridine axis that regulates energy
    • Authors: Yingfeng Deng
      Abstract: Uridine, a pyrimidine nucleoside present at high levels in the plasma of rodents and humans, is critical for RNA synthesis, glycogen deposition, and many other essential cellular processes. It also contributes to systemic metabolism, but the underlying mechanisms remain unclear. We found that plasma uridine levels are regulated by fasting and refeeding in mice, rats, and humans. Fasting increases plasma uridine levels, and this increase relies largely on adipocytes. In contrast, refeeding reduces plasma uridine levels through biliary clearance. Elevation of plasma uridine is required for the drop in body temperature that occurs during fasting. Further, feeding-induced clearance of plasma uridine improves glucose metabolism. We also present findings that implicate leptin signaling in uridine homeostasis and consequent metabolic control and thermoregulation. Our results indicate that plasma uridine governs energy homeostasis and thermoregulation in a mechanism involving adipocyte-dependent uridine biosynthesis and leptin signaling.
      Authors : Yingfeng Deng, Zhao V. Wang, Ruth Gordillo, Yu An, Chen Zhang, Qiren Liang, Jun Yoshino, Kelly M. Cautivo, Jef De Brabander, Joel K. Elmquist, Jay D. Horton, Joseph A. Hill, Samuel Klein, Philipp E. Scherer
      PubDate: 2017-03-17
      DOI: 10.1126/science.aaf5375
  • [Research Article] Stellate cells drive maturation of the
           entorhinal-hippocampal circuit
    • Authors: Flavio Donato
      Abstract: The neural representation of space relies on a network of entorhinal-hippocampal cell types with firing patterns tuned to different abstract features of the environment. To determine how this network is set up during early postnatal development, we monitored markers of structural maturation in developing mice, both in naïve animals and after temporally restricted pharmacogenetic silencing of specific cell populations. We found that entorhinal stellate cells provide an activity-dependent instructive signal that drives maturation sequentially and unidirectionally through the intrinsic circuits of the entorhinal-hippocampal network. The findings raise the possibility that a small number of autonomously developing neuronal populations operate as intrinsic drivers of maturation across widespread regions of the cortex.
      Authors : Flavio Donato, R. Irene Jacobsen, May-Britt Moser, Edvard I. Moser
      PubDate: 2017-03-17
      DOI: 10.1126/science.aai8178
  • [New Products] New Products
    • Abstract: A weekly roundup of information on newly offered instrumentation, apparatus, and laboratory materials of potential interest to researchers.
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1085-a
  • [Business Office Feature] Webinar Deciphering cancer: The intersection of
           epigenetics, metabolism, and tumorigenesis
    • Authors: Kathryn Wellen
      Abstract: Epigenetic modifications to DNA and histone proteins are known to regulate metabolic gene expression, which in turn impacts metabolite levels. Conversely, the machinery responsible for modifying DNA and histones at the epigenetic level is highly sensitive to metabolites arising from cellular metabolism. Thus, the metabolic changes associated with oncogenesis may affect the epigenetic machinery, creating a feedback loop that synergistically promotes the progression of cancer. This webinar will examine how, by targeting proteins responsible for the crosstalk between epigenetics and metabolism, we may be able to develop new and effective therapeutic options for cancer treatment.View the Webinar
      Authors : Kathryn Wellen, Jason Locasale
      Keywords: Science Webinar Series
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1085-b
  • [Editorial] A new cancer ecosystem
    • Authors: Sandra J. Horning
      Abstract: Cancer is increasingly being viewed as an ecosystem, a community in which tumor cells cooperate with other tumor cells and host cells in their microenvironment. As conditions change, the ecosystem evolves and adapts to ensure the survival and growth of cancer. Our understanding of the intricate relationships in this ecosystem has led to revolutionary treatments, including immunotherapy. Successful treatment and prevention of cancer require an ecosystem, too—a coordinated unit of researchers, patients, health care professionals, health care systems, regulatory agencies, government, and industry. How can these partners work together as one interconnected community?Author: Sandra J. Horning
      PubDate: 2017-03-17
      DOI: 10.1126/science.aan1295
  • [In Brief] News at a glance
    • Abstract: In science news around the world, captive Japanese macaques at U.S. research labs may be designated as threatened, a new report finds an increase in the proportion of female researchers globally, an influential Australian climate think tank closes because of lack of funding, Canada weighs a genetic privacy law, and more. Also, one billion dollars in federally funded disease prevention activities would disappear in 2019 under the White House–backed effort by Republicans in Congress to replace the Affordable Care Act. And the first of a trio of autonomous underwater vehicles bearing the moniker Boaty McBoatface sets out on its maiden voyage, to Antarctic waters.
      Keywords: SCI COMMUN
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1104
  • [In Depth] U.K. scientists gird for future break with EU
    • Authors: Erik Stokstad
      Abstract: The United Kingdom is expected to begin the 2-year process of exiting the European Union by the end of March. U.K. researchers are now facing up to the prospect that they won't be able to apply for EU funding or easily recruit postdocs and colleagues from the rest of Europe. To lessen the blow to research, scientists and bureaucrats are already brainstorming about new funding structures and international collaborations that could make up for the lost EU money and brainpower. They are also taking some comfort in a major boost to government R&D funding, detailed last week, aimed at building up research areas that could bolster domestic industries. Yet much uncertainty hangs on what are expected to be rancorous negotiations with the European Union, covering issues such as the right of foreign citizens to remain in the United Kingdom and a possible exit bill from Brussels.Author: Erik Stokstad
      Keywords: Scientific Community
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1107
  • [In Depth] A battle over the ‘best science’
    • Authors: David Malakoff
      Abstract: Who could object to calls for basing government regulations on the "best available science"? But in Washington, D.C., the phrase has become code for a contentious debate surrounding federal regulatory agencies. Last week, the debate heated up again in Congress as a Senate panel launched a potentially arduous effort to spell out how regulators should identify and use the best science. In a related effort, the House of Representatives science panel approved—for the third time in recent years—controversial bills that would require the Environmental Protection Agency (EPA) to make the data underlying all new rules publicly available and affect how it picks its science advisers. The largely Republican backers of the efforts say they are long overdue—and bet any changes have a better chance of becoming law under President Donald Trump, who has promised to streamline and reduce regulation. But observers of the nascent Senate effort—including many scientific societies—are wary, fearing it could end up promoting regulatory paralysis. And critics have blasted the House bills, arguing that they are designed to give industry a disproportionate voice in EPA decisions and cripple the agency's ability to issue rules. "The concern is that a lot of this looks like a clever, stealth attempt to create new legal and administrative pathways for slowing agencies down and tying them up in court, rather than genuinely trying to assure the use of the best science in rulemaking," says Paul Billings, senior vice president for advocacy in the American Lung Association's Washington, D.C., office.Author: David Malakoff
      Keywords: U.S. Policy
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1108
  • [In Depth] iPS cell therapy reported safe
    • Authors: Dennis Normile
      Abstract: Japanese researchers reported this week that the first trial of induced pluripotent stem (iPS) cells in a human has proved safe and effective in halting the progression of age-related macular degeneration (AMD), though there was minimal improvement in vision. AMD is the leading cause of vision loss in the elderly. The team took a skin sample from the patient and derived iPS cells, which can be used to create all the tissues within a body. They differentiated the iPS cells into the kind of retinal tissue damaged by AMD and surgically slipped a small replacement graft into one of the patient's eyes. Starting with the patient's own cells avoids the chance of immune rejection of the new tissue. But deriving such genetically matched cells is so expensive the group will use material from an iPS cell bank for further trials.Author: Dennis Normile
      Keywords: Regenerative Medicine
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1109
  • [In Depth] How plants learned to breathe
    • Authors: Elizabeth Pennisi
      Abstract: Anyone awed by towering redwoods should offer thanks to stomata, the tiny pores on the leaves of all trees and other vascular plants. These microscopic mouths allow plants to grow tall and to regulate carbon dioxide intake and water loss. Stomata, in short, helped plants colonize the landscape and transform the planet. Now, molecular studies are giving scientists glimpses of the early days of stomata and how they have changed since then. They suggest complex stomata evolved to help early plants control moisture in their spore capsules and that other plants later exploited these pores to breathe in carbon dioxide and exhale water vapor. And hundreds of millions of years later, more sophisticated stomata evolved in grasses, enabling them to tightly control water loss—a feature that helped them dominate dry landscapes around the world.Author: Elizabeth Pennisi
      Keywords: Evolution
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1110
  • [In Depth] Earth science a ‘no-brainer’ for NASA's science
    • Authors: Paul Voosen
      Abstract: In October 2016, Thomas Zurbuchen took the reins of NASA's science directorate. A heliophysicist from the University of Michigan in Ann Arbor, Zurbuchen grew up in a tiny Swiss village with more cows than people. Raised in a deeply religious family, he grew comfortable asking the hard questions: "Where am I from?" and "What's my purpose?" He could soon face more hard questions from the administration of U.S. President Donald Trump, which is skeptical about the value of climate change research, much of it supported by NASA. After nearly 6 months on the job, Zurbuchen answers questions on the value of earth science, the role of risk, and how he talks to members of a polarized electorate.Author: Paul Voosen
      Keywords: Q&A
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1112
  • [Feature] Unearthing democracy's roots
    • Authors: Lizzie Wade
      Abstract: For decades, archaeologists thought democratic republics such as classical Athens and medieval Venice were a purely European phenomenon. Conventional wisdom held that in premodern, non-Western societies, despots simply extracted labor and wealth from their subjects. But archaeologists have identified several societies in pre-Columbian Mesoamerica that upend that model. They argue that societies such as Tlaxcallan in the central Mexican highlands and Tres Zapotes along the Mexican gulf coast were organized collectively, meaning that rulers shared power and commoners had a say in the government that presided over their lives. These societies were not necessarily full democracies in which citizens cast votes, but they were radically different from the autocratic, inherited rule found—or assumed—in most ancient societies. Archaeologists now say that these collective societies left telltale traces in their material culture and urban planning, such as repetitive architecture, an emphasis on public space over palaces, reliance on local production over exotic trade goods, and a narrowing of wealth gaps between elites and commoners.Author: Lizzie Wade
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1114
  • [Perspective] Learning from monkey “talk”
    • Authors: Charles T. Snowdon
      Abstract: A fundamental problem for understanding the evolution of human language has been the lack of significant parallels among nonhuman primates. Most researchers have focused on vocal plasticity—that is, the ability to learn novel sounds or modify call structure in response to social or environmental variables. Although songbirds, whales, dolphins, and some other mammals have this ability, nonhuman primates have appeared not to have it (1). Other studies found that nonhuman primates do not have a vocal tract that would allow them to produce the sounds of human speech (2) and that primates cannot take turns, a critical aspect of human conversation (3). All three points have been challenged by recent research (see the table), suggesting that nonhuman primates may after all be valuable models for understanding the evolution of speech and language.Author: Charles T. Snowdon
      Keywords: Language Development
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam7443
  • [Perspective] Genome editors take on crops
    • Authors: Armin Scheben
      Abstract: The global population is expected to rise from 7.3 billion to 9.7 billion by 2050 (1). At the same time, climate change poses increasing risks to crop production through droughts and pests (2). Improved crops are thus urgently needed to meet growing demand for food and address changing climatic conditions. Genome-editing technologies such as the CRISPR (clustered regularly interspaced short palindromic repeat)/Cas (CRISPR-associated protein) system (3) show promise for helping to address these challenges, if the precision of genome editing is improved and the technology is approved and accepted by regulators, producers, and consumers.
      Authors : Armin Scheben, David Edwards
      Keywords: Plant Breeding
      PubDate: 2017-03-17
      DOI: 10.1126/science.aal4680
  • [Perspective] Fat controls U
    • Authors: Martin Jastroch
      Abstract: Uridine (U) is a remarkably important molecule that is essential for a number of evolutionary and biological processes. It consists of the pyrimidine-analog uracil, which is linked to a ribose sugar. Uracil itself can be formed abiotically from pyrimidine, suggesting that this base is a central building block of life. Uridine, by contrast, is a precursor for RNA, thus linking genetic information to the expression of proteins. Importantly, when phosphorylated to uridine triphosphate (UTP), it activates glucose to synthesize glycogen stores and thereby controls glucose metabolism. Uridine also has been implicated in neuron functions and brain processes. On page 1173 of this issue, Deng et al. (1) offer transformative insights into the systemic regulation of circulating uridine and its actions in mammals, with implications for the potential of therapeutic uridine supplementation in general and new precision treatments of metabolic diseases in particular.
      Authors : Martin Jastroch, Matthias H. Tschöp
      Keywords: Metabolism
      PubDate: 2017-03-17
      DOI: 10.1126/science.aan0825
  • [Perspective] Probing the limits of heat flow
    • Authors: Dvira Segal
      Abstract: The existence of universal upper bounds (limits) for the rates of transport of electricity and thermal energy is a striking manifestation of quantum mechanics. These fundamental bounds can be revealed in low-dimensional constrictions defining a single transport channel. The discrete unit (quantum) of electrical conductance G0 has been observed in many experiments dating back to 1988 (1, 2), but the quantum of thermal conductance G0,Th has been much more challenging to probe. Unlike tiny electrical currents, it is much harder to measure minute heat currents in a reproducible manner. On page 1192 of this issue, Cui et al. (3) conquer this challenge by developing an experimental platform for studying quantum thermal transport at the atomic limit. Their work reveals that thermal conductance can be quantized even at room temperature, as well as the fundamental relation between the thermal and electrical conductances. This study paves the way for investigations of thermal phenomena in individual molecular devices, with technological ramifications for controlling energy transport in nanoscale electronic circuitry.Author: Dvira Segal
      Keywords: Nanoscale Transport
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam9362
  • [Perspective] Old moms say, no Sir
    • Authors: Aaron D. Gitler
      Abstract: Is aging ineluctable, or are there genetic programs of aging that could be manipulated to extend life span? Research over the past two decades has provided powerful evidence that aging is indeed regulated by genes that control highly conserved pathways (1). For example, mutations in single genes in model organisms like flies and worms not only allow these animals to live longer, but rejuvenate them as well (2). Even the single-celled budding yeast Saccharomyces cerevisiae ages, and specific genes likewise control this process (1). Indeed, one of the most powerful genetic manipulations to extend life span was discovered in yeast. The histone deacetylase silent information regulator 2 (Sir2) is required for repressing the transcription of certain mating-type loci, telomeres, and ribosomal DNA (3–5). The latter had been linked to aging in yeast, inspiring studies that revealed Sir2's importance for this process (6). Subsequent work in yeast and animal models established that changes in Sir2 activity are responsible for much of the life span–extending effects of caloric restriction (7). On page 1184 of this issue, Schlissel et al. (8) report that a particular facet of aging, which had long been attributed to age-dependent changes in Sir2 function, is caused by a new mechanism.
      Authors : Aaron D. Gitler, Daniel F. Jarosz
      Keywords: Aging
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam9740
  • [Perspective] Atoms on the move—finding the hydrogen
    • Authors: Julie Cairney
      Abstract: Hydrogen wreaks havoc in many alloy systems, leading to embrittlement that can cause catastrophic failure. This is a serious issue for any industry that produces or uses hydrogen—affecting production, transport, storage, and use—and is a real challenge for the development of a hydrogen economy. However, the design of new materials that resist hydrogen embrittlement is limited by the difficulty of experimentally measuring or observing hydrogen; precisely locating hydrogen at the atomic scale is a notorious challenge in materials science. Other examples of where this information is required include the development of fuel cells, the prevention of corrosion, and the improvement of catalytic processes. On page 1196 of this issue, Chen et al. (1) directly observe the precise, atomic-scale, three-dimensional (3D) distribution of hydrogen atoms within matter by using a new approach to atom probe tomography that utilizes deuteration, cryogenic transfer, and sophisticated data-analysis algorithms.Author: Julie Cairney
      Keywords: Materials Science
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam8616
  • [Perspective] Developing an HIV vaccine
    • Authors: Barton F. Haynes
      Abstract: In 2015, 17 million HIV-infected individuals worldwide were on antiretroviral drug therapies, which are remarkably effective in suppressing the virus. Yet, 6000 people a day became newly infected, making the quest for an effective and safe HIV vaccine a major global priority. However, developing a vaccine has been difficult for reasons related to the nature of the virus and its life cycle, including early integration into the host genome and the highly glycosylated, compact, and sequence-variable nature of the envelope (Env) “spike” that is the sole target of neutralizing antibodies (and typically associated with vaccine protection). Where are we, then, on the path to a vaccine?
      Authors : Barton F. Haynes, Dennis R. Burton
      Keywords: HIV
      PubDate: 2017-03-17
      DOI: 10.1126/science.aan0662
  • [Policy Forum] How economics can shape precision medicines
    • Authors: A. D. Stern
      Abstract: Many public and private efforts in coming years will focus on research in precision medicine, developing biomarkers to indicate which patients are likely to benefit from a certain treatment so that others can be spared the cost—financial and physical—of being treated with unproductive therapies and therapeutic signals can be more easily uncovered. However, such research initiatives alone will not deliver new medicines to patients in the absence of strong incentives to bring new products to market. We examine the unique economics of precision medicines and associated biomarkers, with an emphasis on the factors affecting their development, pricing, and access.
      Authors : A. D. Stern, B. M. Alexander, A. Chandra
      Keywords: Biomedical Innovation
      PubDate: 2017-03-17
      DOI: 10.1126/science.aai8707
  • [Book Review] The next New York
    • Authors: Carl Abbott
      Abstract: In his new "cli-fi" novel New York 2140, Kim Stanley Robinson envisions a future New York in which the city's streets have been transformed by rising oceans into busy canals, and skyscrapers built on bedrock have sealed their lower floors but continue to function. The story unfolds through the overlapping lives of the residents of the Metropolitan Life Tower, who come together to prevent economic disaster in the wake of the collapse of a bubble in "intertidal" real estate. Filled with guarded optimism about our capacity to meet daunting challenges, the novel invites readers to imagine our own 21st-century future.Author: Carl Abbott
      Keywords: Fiction
      PubDate: 2017-03-17
      DOI: 10.1126/science.aal4576
  • [Book Review] Our synthetic moment
    • Authors: Luis Campos
      Abstract: "It is at times hard to distill that which unites the people and projects that travel under the name 'synthetic biology,'" Sophia Roosth notes in Synthetic: How Life Got Made, but that doesn't stop her from following the field in flux, tracking "brave new organisms" (and those who make them) through classrooms and industrial laboratories from Boston to the Bay Area and from neighborhood bars to far-flung conferences. A chimera of anthropology bred with a dash of history, Synthetic reads synthetic biology's constructs both as "materialized theories" and as "postcards from a particular cultural moment."Author: Luis Campos
      Keywords: Synthetic Biology
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam6893
  • [Letter] Mexican and U.S. scientists: Partners
    • Authors: Antonio Lazcano
      Authors : Antonio Lazcano, Adriana Ortiz Ortega, Saúl Armendariz
      PubDate: 2017-03-17
      DOI: 10.1126/science.aan0569
  • [Letter] Lessons from the Oroville dam
    • Authors: Farshid Vahedifard
      Authors : Farshid Vahedifard, Amir AghaKouchak, Elisa Ragno, Shahriar Shahrokhabadi, Iman Mallakpour
      PubDate: 2017-03-17
      DOI: 10.1126/science.aan0171
  • [Letter] Science Story Bank: Submit Now!
    • PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1140
  • [Letter] Carbon sequestration beyond tree longevity
    • Authors: Lucas C. R. Silva
      Abstract: Author: Lucas C. R. Silva
      PubDate: 2017-03-17
      DOI: 10.1126/science.aan0109
  • [Introduction to Special Issue] Stocking oncology's medicine cabinet
    • Authors: Paula A. Kiberstis
      Authors : Paula A. Kiberstis, John Travis
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1142
  • [Special Issue News] When less is more
    • Authors: Jocelyn Kaiser
      Abstract: For decades, cancer treatments have been given to patients continually at the maximum dose that can be tolerated. But a few labs are challenging that dogma. They are motivated by theoretical models of cancer growth and evidence from animal studies suggesting that briefly stopping or cutting back a drug dose can help keep the cancer cells from becoming resistant to the drug and can even trigger some cells to die, extending patients' lives. Periodically ceasing cancer therapy can also be less toxic for the patient. Trials are testing these new dosing strategies. Some stop the drug altogether, then restart it on a fixed schedule; others alternate high and low doses; and still others wait until the tumor has shrunk significantly before dialing down treatment.Author: Jocelyn Kaiser
      Keywords: Frontiers in Cancer Therapy
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1144
  • [Special Issue Review] The cancer epigenome: Concepts, challenges, and
           therapeutic opportunities
    • Authors: Mark A. Dawson
      Abstract: Cancer biology is profoundly influenced by changes in the epigenome. Because the dynamic plasticity of the epigenome lends itself well to therapeutic manipulation, the past few years have witnessed an unprecedented investment in the development, characterization, and translation of targeted epigenetic therapies. In this review, I provide a broad context for recent developments that offer a greater understanding of how epigenetic regulators facilitate the initiation, maintenance, and evolution of cancer. I discuss newly developed epigenetic therapies and the cellular and molecular mechanisms that may govern sensitivity and resistance to these agents. I also review the rationale for future combination therapies involving existing and emerging epigenetic drugs.Author: Mark A. Dawson
      Keywords: Frontiers in Cancer Therapy
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam7304
  • [Special Issue Review] PARP inhibitors: Synthetic lethality in the clinic
    • Authors: Christopher J. Lord
      Abstract: PARP inhibitors (PARPi), a cancer therapy targeting poly(ADP-ribose) polymerase, are the first clinically approved drugs designed to exploit synthetic lethality, a genetic concept proposed nearly a century ago. Tumors arising in patients who carry germline mutations in either BRCA1 or BRCA2 are sensitive to PARPi because they have a specific type of DNA repair defect. PARPi also show promising activity in more common cancers that share this repair defect. However, as with other targeted therapies, resistance to PARPi arises in advanced disease. In addition, determining the optimal use of PARPi within drug combination approaches has been challenging. Nevertheless, the preclinical discovery of PARPi synthetic lethality and the route to clinical approval provide interesting lessons for the development of other therapies. Here, we discuss current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness.
      Authors : Christopher J. Lord, Alan Ashworth
      Keywords: Frontiers in Cancer Therapy
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam7344
  • [Special Issue Review] Drugging RAS: Know the enemy
    • Authors: Bjoern Papke
      Abstract: The three RAS oncogenes make up the most frequently mutated gene family in human cancer. The well-validated role of mutationally activated RAS genes in driving cancer development and growth has stimulated comprehensive efforts to develop therapeutic strategies to block mutant RAS function for cancer treatment. Disappointingly, despite more than three decades of research effort, clinically effective anti-RAS therapies have remained elusive, prompting a perception that RAS may be undruggable. However, with a greater appreciation of the complexities of RAS that thwarted past efforts, and armed with new technologies and directions, the field is experiencing renewed excitement that mutant RAS may finally be conquered. Here we summarize where these efforts stand.
      Authors : Bjoern Papke, Channing J. Der
      Keywords: Frontiers in Cancer Therapy
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam7622
  • [Special Issue Review] Waste disposal—An attractive strategy for
           cancer therapy
    • Authors: Jemilat Salami
      Abstract: Targeted therapies for cancer are typically small molecules or monoclonal antibodies that act by inhibiting the activity of specific proteins that drive tumor growth. Although many of these drugs are effective in cancer patients, the response is often not durable because tumor cells develop resistance to the drugs. Another limitation of this strategy is that not all oncogenic driver proteins are “druggable” enzymes or receptors with activities that can be inhibited. Here we describe an alternative approach to targeted therapy that is based on co-opting the cellular quality-control machinery—the ubiquitin-proteasome system—to remove specific cancer-causing proteins from the cell. We first discuss examples of existing cancer drugs that work by degrading specific proteins and then review recent progress in the rational design and preclinical testing of small molecules that induce selective degradation of specific target proteins.
      Authors : Jemilat Salami, Craig M. Crews
      Keywords: Frontiers in Cancer Therapy
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam7340
  • [This Week in Science] Making more of your stomata
    • Authors: Pamela J. Hines
      Abstract: Author: Pamela J. Hines
      Keywords: Plant Science
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-a
  • [This Week in Science] Molecular clockwork from cyanobacteria
    • Authors: L. Bryan Ray
      Abstract: Author: L. Bryan Ray
      Keywords: Circadian Rhythms
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-b
  • [This Week in Science] Lifting off gold films
    • Authors: Phil Szuromi
      Abstract: Author: Phil Szuromi
      Keywords: Nanomaterials
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-c
  • [This Week in Science] Archean cratons get a Hadean mash-up
    • Authors: Brent Grocholski
      Abstract: Author: Brent Grocholski
      Keywords: Geochemistry
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-d
  • [This Week in Science] Putting plasmons in a spin
    • Authors: Ian S. Osborne
      Abstract: Author: Ian S. Osborne
      Keywords: Nanophotonics
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-e
  • [This Week in Science] Countering TB prodrug resistance
    • Authors: Caroline Ash
      Abstract: Author: Caroline Ash
      Keywords: Antibiotics
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-f
  • [This Week in Science] Finding the right blood type
    • Authors: Caitlin Czajka
      Abstract: Author: Caitlin Czajka
      Keywords: Diagnostics
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-g
  • [This Week in Science] The parasite of my parasite is my friend?
    • Authors: Caroline Ash
      Abstract: Author: Caroline Ash
      Keywords: Infection
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-h
  • [This Week in Science] Sensing touch without touching
    • Authors: Lynden Archer
      Abstract: Author: Lynden Archer
      Keywords: Wearable Technology
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-i
  • [This Week in Science] The lights go on in order
    • Authors: Pamela J. Hines
      Abstract: Author: Pamela J. Hines
      Keywords: Neurodevelopment
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-j
  • [This Week in Science] Uridine's rise and fall: Food for thought
    • Authors: Paula A. Kiberstis
      Abstract: Author: Paula A. Kiberstis
      Keywords: Physiology
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-k
  • [This Week in Science] Heavy hydrogen gets frozen in place
    • Authors: Brent Grocholski
      Abstract: Author: Brent Grocholski
      Keywords: Metallurgy
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-l
  • [This Week in Science] Calorimetry reaches an atomic junction
    • Authors: Brent Grocholski
      Abstract: Author: Brent Grocholski
      Keywords: Nanoscale Transport
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-m
  • [This Week in Science] Protein aggregation-mediated aging in yeast
    • Authors: L. Bryan Ray
      Abstract: Author: L. Bryan Ray
      Keywords: Aging
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-n
  • [This Week in Science] Promise and challenges of gene editing
    • Authors: Julia Fahrenkamp-Uppenbrink
      Abstract: Author: Julia Fahrenkamp-Uppenbrink
      Keywords: Crop Development
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-o
  • [This Week in Science] Nonhuman primates model language evolution
    • Authors: Julia Fahrenkamp-Uppenbrink
      Abstract: Author: Julia Fahrenkamp-Uppenbrink
      Keywords: Language Development
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-p
  • [This Week in Science] Melanoma cells talk to keratinocytes
    • Authors: Leslie K. Ferrarelli
      Abstract: Author: Leslie K. Ferrarelli
      Keywords: Cancer
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-q
  • [This Week in Science] NK cells in severe asthma: Failed resolution
    • Authors: Angela Colmone
      Abstract: Author: Angela Colmone
      Keywords: Asthma
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1169-r
  • [Editors' Choice] Remote sensing for analyzing smallholder farm yields
    • Authors: Pamela J. Hines
      Abstract: Author: Pamela J. Hines
      Keywords: Agriculture
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1170-a
  • [Editors' Choice] Sand-driven magnetic field
    • Authors: Brent Grocholski
      Abstract: Author: Brent Grocholski
      Keywords: Geophysics
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1170-b
  • [Editors' Choice] Microaggression actions outpace evidence
    • Authors: Brad Wible
      Abstract: Author: Brad Wible
      Keywords: Psychology
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1170-c
  • [Editors' Choice] Softening up your target
    • Authors: Stella M. Hurtley
      Abstract: Author: Stella M. Hurtley
      Keywords: Malaria
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1170-d
  • [Editors' Choice] Restacking the deck
    • Authors: Phil Szuromi
      Abstract: Author: Phil Szuromi
      Keywords: Nanomaterials
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1170-e
  • [Editors' Choice] Love hormones and mental health
    • Authors: Megan Eldred
      Abstract: Author: Megan Eldred
      Keywords: Neurodevelopment
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1170-f
  • [Editors' Choice] Fine-scale structure in higher brain areas
    • Authors: Peter Stern
      Abstract: Author: Peter Stern
      Keywords: Neuroscience
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1170-g
  • [Research Article] Structural basis of the day-night transition in a
           bacterial circadian clock
    • Authors: Roger Tseng
      Abstract: Circadian clocks are ubiquitous timing systems that induce rhythms of biological activities in synchrony with night and day. In cyanobacteria, timing is generated by a posttranslational clock consisting of KaiA, KaiB, and KaiC proteins and a set of output signaling proteins, SasA and CikA, which transduce this rhythm to control gene expression. Here, we describe crystal and nuclear magnetic resonance structures of KaiB-KaiC,KaiA-KaiB-KaiC, and CikA-KaiB complexes. They reveal how the metamorphic properties of KaiB, a protein that adopts two distinct folds, and the post–adenosine triphosphate hydrolysis state of KaiC create a hub around which nighttime signaling events revolve, including inactivation of KaiA and reciprocal regulation of the mutually antagonistic signaling proteins, SasA and CikA.
      Authors : Roger Tseng, Nicolette F. Goularte, Archana Chavan, Jansen Luu, Susan E. Cohen, Yong-Gang Chang, Joel Heisler, Sheng Li, Alicia K. Michael, Sarvind Tripathi, Susan S. Golden, Andy LiWang, Carrie L. Partch
      PubDate: 2017-03-17
      DOI: 10.1126/science.aag2516
  • [Report] Structures of the cyanobacterial circadian oscillator frozen in a
           fully assembled state
    • Authors: Joost Snijder
      Abstract: Cyanobacteria have a robust circadian oscillator, known as the Kai system. Reconstituted from the purified protein components KaiC, KaiB, and KaiA, it can tick autonomously in the presence of adenosine 5′-triphosphate (ATP). The KaiC hexamers enter a natural 24-hour reaction cycle of autophosphorylation and assembly with KaiB and KaiA in numerous diverse forms. We describe the preparation of stoichiometrically well-defined assemblies of KaiCB and KaiCBA, as monitored by native mass spectrometry, allowing for a structural characterization by single-particle cryo–electron microscopy and mass spectrometry. Our data reveal details of the interactions between the Kai proteins and provide a structural basis to understand periodic assembly of the protein oscillator.
      Authors : Joost Snijder, Jan M. Schuller, Anika Wiegard, Philip Lössl, Nicolas Schmelling, Ilka M. Axmann, Jürgen M. Plitzko, Friedrich Förster, Albert J. R. Heck
      PubDate: 2017-03-17
      DOI: 10.1126/science.aag3218
  • [Report] Aggregation of the Whi3 protein, not loss of heterochromatin,
           causes sterility in old yeast cells
    • Authors: Gavin Schlissel
      Abstract: In yeast, heterochromatin silencing is reported to decline in aging mother cells, causing sterility in old cells. This process is thought to reflect a decrease in the activity of the NAD+ (oxidized nicotinamide adenine dinucleotide)–dependent deacetylase Sir2. We tested whether Sir2 becomes nonfunctional gradually or precipitously during aging. Unexpectedly, silencing of the heterochromatic HML and HMR loci was not lost during aging. Old cells could initiate a mating response; however, they were less sensitive to mating pheromone than were young cells because of age-dependent aggregation of Whi3, an RNA-binding protein controlling S-phase entry. Removing the polyglutamine domain of Whi3 restored the pheromone sensitivity of old cells. We propose that aging phenotypes previously attributed to loss of heterochromatin silencing are instead caused by aggregation of the Whi3 cell cycle regulator.
      Authors : Gavin Schlissel, Marek K. Krzyzanowski, Fabrice Caudron, Yves Barral, Jasper Rine
      PubDate: 2017-03-17
      DOI: 10.1126/science.aaj2103
  • [Report] Revealing the subfemtosecond dynamics of orbital angular momentum
           in nanoplasmonic vortices
    • Authors: G. Spektor
      Abstract: The ability of light to carry and deliver orbital angular momentum (OAM) in the form of optical vortices has attracted much interest. The physical properties of light with a helical wavefront can be confined onto two-dimensional surfaces with subwavelength dimensions in the form of plasmonic vortices, opening avenues for thus far unknown light-matter interactions. Because of their extreme rotational velocity, the ultrafast dynamics of such vortices remained unexplored. Here we show the detailed spatiotemporal evolution of nanovortices using time-resolved two-photon photoemission electron microscopy. We observe both long- and short-range plasmonic vortices confined to deep subwavelength dimensions on the scale of 100 nanometers with nanometer spatial resolution and subfemtosecond time-step resolution. Finally, by measuring the angular velocity of the vortex, we directly extract the OAM magnitude of light.
      Authors : G. Spektor, D. Kilbane, A. K. Mahro, B. Frank, S. Ristok, L. Gal, P. Kahl, D. Podbiel, S. Mathias, H. Giessen, F.-J. Meyer zu Heringdorf, M. Orenstein, M. Aeschlimann
      PubDate: 2017-03-17
      DOI: 10.1126/science.aaj1699
  • [Report] Quantized thermal transport in single-atom junctions
    • Authors: Longji Cui
      Abstract: Thermal transport in individual atomic junctions and chains is of great fundamental interest because of the distinctive quantum effects expected to arise in them. By using novel, custom-fabricated, picowatt-resolution calorimetric scanning probes, we measured the thermal conductance of gold and platinum metallic wires down to single-atom junctions. Our work reveals that the thermal conductance of gold single-atom junctions is quantized at room temperature and shows that the Wiedemann-Franz law relating thermal and electrical conductance is satisfied even in single-atom contacts. Furthermore, we quantitatively explain our experimental results within the Landauer framework for quantum thermal transport. The experimental techniques reported here will enable thermal transport studies in atomic and molecular chains, which will be key to investigating numerous fundamental issues that thus far have remained experimentally inaccessible.
      Authors : Longji Cui, Wonho Jeong, Sunghoon Hur, Manuel Matt, Jan C. Klöckner, Fabian Pauly, Peter Nielaba, Juan Carlos Cuevas, Edgar Meyhofer, Pramod Reddy
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam6622
  • [Report] Direct observation of individual hydrogen atoms at trapping sites
           in a ferritic steel
    • Authors: Y.-S. Chen
      Abstract: The design of atomic-scale microstructural traps to limit the diffusion of hydrogen is one key strategy in the development of hydrogen-embrittlement–resistant materials. In the case of bearing steels, an effective trapping mechanism may be the incorporation of finely dispersed V-Mo-Nb carbides in a ferrite matrix. First, we charged a ferritic steel with deuterium by means of electrolytic loading to achieve a high hydrogen concentration. We then immobilized it in the microstructure with a cryogenic transfer protocol before atom probe tomography (APT) analysis. Using APT, we show trapping of hydrogen within the core of these carbides with quantitative composition profiles. Furthermore, with this method the experiment can be feasibly replicated in any APT-equipped laboratory by using a simple cold chain.
      Authors : Y.-S. Chen, D. Haley, S. S. A. Gerstl, A. J. London, F. Sweeney, R. A. Wepf, W. M. Rainforth, P. A. J. Bagot, M. P. Moody
      PubDate: 2017-03-17
      DOI: 10.1126/science.aal2418
  • [Report] Building Archean cratons from Hadean mafic crust
    • Authors: Jonathan O’Neil
      Abstract: Geologic processing of Earth’s surface has removed most of the evidence concerning the nature of Earth’s first crust. One region of ancient crust is the Hudson Bay terrane of northeastern Canada, which is mainly composed of Neoarchean felsic crust and forms the nucleus of the Northeastern Superior Province. New data show these ~2.7-billion-year-old rocks to be the youngest to yield variability in neodymium-142 (142Nd), the decay product of short-lived samarium-146 (146Sm). Combined 146-147Sm-142-143Nd data reveal that this large block of Archean crust formed by reworking of much older (>4.2 billion-year-old) mafic crust over a 1.5-billion-year interval of early Earth history. Thus, unlike on modern Earth, mafic crust apparently could survive for more than 1 billion years to form an important source rock for Archean crustal genesis.
      Authors : Jonathan O’Neil, Richard W. Carlson
      PubDate: 2017-03-17
      DOI: 10.1126/science.aah3823
  • [Report] Epitaxial lift-off of electrodeposited single-crystal gold foils
           for flexible electronics
    • Authors: Naveen K. Mahenderkar
      Abstract: We introduce a simple and inexpensive procedure for epitaxial lift-off of wafer-size flexible and transparent foils of single-crystal gold using silicon as a template. Lateral electrochemical undergrowth of a sacrificial SiOx layer was achieved by photoelectrochemically oxidizing silicon under light irradiation. A 28-nanometer-thick gold foil with a sheet resistance of 7 ohms per square showed only a 4% increase in resistance after 4000 bending cycles. A flexible organic light-emitting diode based on tris(bipyridyl)ruthenium(II) that was spin-coated on a foil exploited the transmittance and flexibility of the gold foil. Cuprous oxide as an inorganic semiconductor that was epitaxially electrodeposited onto the gold foils exhibited a diode quality factor n of 1.6 (where n = 1.0 for an ideal diode), compared with a value of 3.1 for a polycrystalline deposit. Zinc oxide nanowires electrodeposited epitaxially on a gold foil also showed flexibility, with the nanowires intact up to 500 bending cycles.
      Authors : Naveen K. Mahenderkar, Qingzhi Chen, Ying-Chau Liu, Alexander R. Duchild, Seth Hofheins, Eric Chason, Jay A. Switzer
      PubDate: 2017-03-17
      DOI: 10.1126/science.aam5830
  • [Report] Reversion of antibiotic resistance in Mycobacterium tuberculosis
           by spiroisoxazoline SMARt-420
    • Authors: Nicolas Blondiaux
      Abstract: Antibiotic resistance is one of the biggest threats to human health globally. Alarmingly, multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis have now spread worldwide. Some key antituberculosis antibiotics are prodrugs, for which resistance mechanisms are mainly driven by mutations in the bacterial enzymatic pathway required for their bioactivation. We have developed drug-like molecules that activate a cryptic alternative bioactivation pathway of ethionamide in M. tuberculosis, circumventing the classic activation pathway in which resistance mutations have now been observed. The first-of-its-kind molecule, named SMARt-420 (Small Molecule Aborting Resistance), not only fully reverses ethionamide-acquired resistance and clears ethionamide-resistant infection in mice, it also increases the basal sensitivity of bacteria to ethionamide.
      Authors : Nicolas Blondiaux, Martin Moune, Matthieu Desroses, Rosangela Frita, Marion Flipo, Vanessa Mathys, Karine Soetaert, Mehdi Kiass, Vincent Delorme, Kamel Djaout, Vincent Trebosc, Christian Kemmer, René Wintjens, Alexandre Wohlkönig, Rudy Antoine, Ludovic Huot, David Hot, Mireia Coscolla, Julia Feldmann, Sebastien Gagneux, Camille Locht, Priscille Brodin, Marc Gitzinger, Benoit Déprez, Nicolas Willand, Alain R. Baulard
      PubDate: 2017-03-17
      DOI: 10.1126/science.aag1006
  • [Report] Inflammation boosts bacteriophage transfer between Salmonella
    • Authors: Médéric Diard
      Abstract: Bacteriophage transfer (lysogenic conversion) promotes bacterial virulence evolution. There is limited understanding of the factors that determine lysogenic conversion dynamics within infected hosts. A murine Salmonella Typhimurium (S.Tm) diarrhea model was used to study the transfer of SopEΦ, a prophage from S.Tm SL1344, to S.Tm ATCC14028S. Gut inflammation and enteric disease triggered >55% lysogenic conversion of ATCC14028S within 3 days. Without inflammation, SopEΦ transfer was reduced by up to 105-fold. This was because inflammation (e.g., reactive oxygen species, reactive nitrogen species, hypochlorite) triggers the bacterial SOS response, boosts expression of the phage antirepressor Tum, and thereby promotes free phage production and subsequent transfer. Mucosal vaccination prevented a dense intestinal S.Tm population from inducing inflammation and consequently abolished SopEΦ transfer. Vaccination may be a general strategy for blocking pathogen evolution that requires disease-driven transfer of temperate bacteriophages.
      Authors : Médéric Diard, Erik Bakkeren, Jeffrey K. Cornuault, Kathrin Moor, Annika Hausmann, Mikael E. Sellin, Claude Loverdo, Abram Aertsen, Martin Ackermann, Marianne De Paepe, Emma Slack, Wolf-Dietrich Hardt
      PubDate: 2017-03-17
      DOI: 10.1126/science.aaf8451
  • [Report] Mobile MUTE specifies subsidiary cells to build physiologically
           improved grass stomata
    • Authors: Michael T. Raissig
      Abstract: Plants optimize carbon assimilation while limiting water loss by adjusting stomatal aperture. In grasses, a developmental innovation—the addition of subsidiary cells (SCs) flanking two dumbbell-shaped guard cells (GCs)—is linked to improved stomatal physiology. Here, we identify a transcription factor necessary and sufficient for SC formation in the wheat relative Brachypodium distachyon. Unexpectedly, the transcription factor is an ortholog of the stomatal regulator AtMUTE, which defines GC precursor fate in Arabidopsis. The novel role of BdMUTE in specifying lateral SCs appears linked to its acquisition of cell-to-cell mobility in Brachypodium. Physiological analyses on SC-less plants experimentally support classic hypotheses that SCs permit greater stomatal responsiveness and larger range of pore apertures. Manipulation of SC formation and function in crops, therefore, may be an effective approach to enhance plant performance.
      Authors : Michael T. Raissig, Juliana L. Matos, M. Ximena Anleu Gil, Ari Kornfeld, Akhila Bettadapur, Emily Abrash, Hannah R. Allison, Grayson Badgley, John P. Vogel, Joseph A. Berry, Dominique C. Bergmann
      PubDate: 2017-03-17
      DOI: 10.1126/science.aal3254
  • [Business Office Feature] Cancer immunotherapy comes of age
    • Authors: Amber Dance
      Abstract: Oncologists have long rested their treatment plans on three so-called "pillars"—chemotherapy, surgery, and radiation. But in recent years, scientists have been busily erecting a fourth pillar: immunotherapy. The idea of harnessing the immune system to fight cancer has already moved from the lab to the clinic, thanks to technologies such as checkpoint inhibitors and genetically engineered immune cells. Read the Feature (Full-Text HTML)Read the Feature (PDF)Read New Products (PDF)Author: Amber Dance
      Keywords: Business Office Feature
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1220
  • [Working Life] Step out of the lab and engage
    • Authors: Gabrielle Kardon
      Abstract: Author: Gabrielle Kardon
      PubDate: 2017-03-17
      DOI: 10.1126/science.355.6330.1234
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