Many decades after their discoveries, the basic building blocks of the atomic nucleus—the proton and the neutron—remain among the most mysterious of subatomic particles. In the cartoon view, the positively charged proton and the uncharged neutron both consist of trios of particles called up quarks and down quarks. In actuality, each is a pullulating mass of countless quarks, antiquarks, and gluons, massless particles that convey the strong nuclear force that holds quarks together. A nucleon is so messy that physicists can't say exactly how its most basic properties, such as its mass and spin, emerge from the tangle. But now physicists at Thomas Jefferson National Accelerator Facility here are finishing a $338 million upgrade to their particle accelerator, the Continuous Electron Beam Accelerator Facility, to double its energy and probe the innards of protons and neutrons with unprecedented precision. In the coming decade, a mosaic of measurements may finally give physicists a clearer view into the proton and the neutron. Author: Adrian Cho

From a small wooden desk in a row home a few miles north of the U.S. Capitol, Justin Goodman is waging war against animal research as director of laboratory investigations at People for the Ethical Treatment of Animals. Whereas other activists stick to protests and publicity stunts, he and his team have spent the past 5 years challenging scientists on their own turf. In talks and papers published in the peer-reviewed literature, they marshal data in an attempt to show researchers that animal experimentation is flawed, cruel, and just plain worthless. Goodman's papers have questioned the validity of the university committees that oversee animal research, encouraged U.S. allies to explore alternatives to animals in military medical training, and wounded the reputation of the world's largest accreditor of lab animal welfare. But many scientists are unswayed, saying that the work is methodologically flawed and deeply misleading. They say that despite the veneer of science, Goodman's studies are anything but. Author: David Grimm

Some discoveries are new, others old. Here, we consider one of each from NASA's Curiosity rover. The new discovery, reported by Mahaffy et al. (1) on page 412 of this issue, is a remarkable measurement of the deuterium-hydrogen (D/H) ratio in a Gale crater mudstone from 3 billion years ago. On page 415, Webster et al. (2) report on the latest chapter in the muddy matter of methane on Mars. What links them is that both were made using the tunable laser spectrometer (TLS), part of the SAM (Sample Analysis at Mars) package on the rover. Author: Kevin Zahnle

Different types of T lymphocytes play a key role in many immune responses, such as killing virally infected or cancerous cells directly, inducing high-affinity antibody responses in B cells, and increasing or decreasing responses from other immune cells. This multiplicity of roles may relate to their recognition properties, which are very difficult to evade. Moreover, cells are very diverse—for CD4+ T cells alone, there are at least six distinct subtypes. This raises the question of just how these different T cells are produced. Early evidence indicated that the type of T cell that dominates the response was dependent on the type of pathogen and route of entry (1, 2). However, over the past several years, more and more flexibility has been observed in a T cell's phenotype (3, 4). On page 400 of this issue, Becattini et al. (5) show that this flexibility is more the rule rather than the exception. Author: Mark M. Davis

The drug resistance specter looms over most infectious diseases. Malaria provides a particularly urgent example of increasing resistance and treatment failure. In the past decade, artemisinin combination therapies (ACTs) have contributed to impressive reductions in malaria morbidity and mortality (1). However, in 2009, Dondorp et al. found that when patients in western Cambodia infected with Plasmodium falciparum (the deadliest form of malaria) were treated with ACTs, they took longer than normal to clear their parasites. It is the artemisinin component that normally clears parasites quickly, and the authors therefore concluded that this component of the ACT was compromised (2). Slow-clearing parasites were also found in western Thailand and other parts of Cambodia (see the first figure) (3, 4). Two reports in this issue, by Mok et al. (page 431) (5) and Straimer et al. (page 428) (6), apply specialized techniques to better understand the mechanisms that underlie this resistance to artemisinins. Author: Carol Hopkins Sibley

In advance of a critical Framework Convention on Tobacco Control (FCTC) held in October 2014, two groups of scientists and public health experts launched a global battle royal over electronic cigarettes—devices that heat liquid nicotine but involve no tobacco. Authors: Amy L. Fairchild, Ronald Bayer

Brazil'fs Soy Moratorium (SoyM) was the first voluntary zero-deforestation agreement implemented in the tropics and set the stage for supply-chain governance of other commodities, such as beef and palm oil [supplementary material (SM)]. In response to pressure from retailers and nongovernmental organizations (NGOs), major soybean traders signed the SoyM, agreeing not to purchase soy grown on lands deforested after July 2006 in the Brazilian Amazon. The soy industry recently extended the SoyM to May 2016, by which time they assert that Brazil'fs environmental governance, such as the increased enforcement and national implementation of the Rural Environmental Registry of private properties (Portuguese acronym CAR) mandated by the Forest Code (FC) (1), will be robust enough to justify ending the agreement (2). We argue that a longer-term commitment is needed to help maintain deforestation-free soy supply chains, as full compliance and enforcement of these regulations is likely years away. Ending the SoyM prematurely would risk a return to deforestation for soy expansion at a time when companies are committing to zero-deforestation supply chains (3). Authors: H. K. Gibbs, L. Rausch, J. Munger, I. Schelly, D. C. Morton, P. Noojipady, B. Soares-Filho, P. Barreto, L. Micol, N. F. Walker

Recent scientific data suggests that human prosocial behavior is more than just a product of education, culture, and religion. Instead, it seems that the seeds of morality may have a long history in our brains. Frans B. M. de Waal welcomes an accessible introduction to the biology and neuroscience of prosociality in a review of The Altruistic Brain: How We Are Naturally Good. Author: Frans B. M. de Waal

Spurred by concerns that the American education system was failing to keep pace with the Soviets after the "Sputnik crisis" of the late 1950s, a dramatic change occurred in the mathematics that was taught in American schools in the 1960s. This "new math", as it was known, was controversial from the start and ultimately short-lived. Jeremy Kilpatrick takes a second look at this contentious era in a review of The New Math: A Political History. Author: Jeremy Kilpatrick

Authors: M. G. G. T. Taylor, C. Alexander, N. Altobelli, M. Fulle, M. Fulchignoni, E. Grün, P. Weissman

Enabled by recently gained understanding of deep-seated and surficial Earth processes, a convergence of views between geophysics and sedimentary geology has been quietly taking place over the past several decades. Surface topography resulting from lithospheric memory, retained at various temporal and spatial scales, has become the connective link between these two methodologically diverse geoscience disciplines. Ideas leading to the hypothesis of plate tectonics originated largely with an oceanic focus, where dynamic and mostly horizontal movements of the crust could be envisioned. But when these notions were applied to the landscapes of the supposedly rigid plate interiors, there was less success in explaining the observed anomalies in terrestrial topography. Solid-Earth geophysics has now reached a developmental stage where vertical movements can be measured and modeled at meaningful scales and the deep-seated structures can be imaged with increasing resolution. Concurrently, there have been advances in quantifying mechanical properties of the lithosphere (the solid outer skin of Earth, usually defined to include both the crust and the solid but elastic upper mantle above the asthenosphere). The lithosphere acts as the intermediary that transfers the effects of mantle dynamics to the surface. These developments have allowed us to better understand the previously puzzling topographic features of plate interiors and continental margins. On the sedimentary geology side, new quantitative modeling techniques and holistic approaches to integrating source-to-sink sedimentary systems have led to clearer understanding of basin evolution and sediment budgets that allow the reconstruction of missing sedimentary records and past geological landscapes. Authors: Sierd Cloetingh, Bilal U. Haq

Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray–based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body. Authors: Mathias Uhlén, Linn Fagerberg, Björn M. Hallström, Cecilia Lindskog, Per Oksvold, Adil Mardinoglu, Åsa Sivertsson, Caroline Kampf, Evelina Sjöstedt, Anna Asplund, IngMarie Olsson, Karolina Edlund, Emma Lundberg, Sanjay Navani, Cristina Al-Khalili Szigyarto, Jacob Odeberg, Dijana Djureinovic, Jenny Ottosson Takanen, Sophia Hober, Tove Alm, Per-Henrik Edqvist, Holger Berling, Hanna Tegel, Jan Mulder, Johan Rockberg, Peter Nilsson, Jochen M. Schwenk, Marica Hamsten, Kalle von Feilitzen, Mattias Forsberg, Lukas Persson, Fredric Johansson, Martin Zwahlen, Gunnar von Heijne, Jens Nielsen, Fredrik Pontén

The distinctly human ability for forceful precision and power “squeeze” gripping is linked to two key evolutionary transitions in hand use: a reduction in arboreal climbing and the manufacture and use of tools. However, it is unclear when these locomotory and manipulative transitions occurred. Here we show that Australopithecus africanus (~3 to 2 million years ago) and several Pleistocene hominins, traditionally considered not to have engaged in habitual tool manufacture, have a human-like trabecular bone pattern in the metacarpals consistent with forceful opposition of the thumb and fingers typically adopted during tool use. These results support archaeological evidence for stone tool use in australopiths and provide morphological evidence that Pliocene hominins achieved human-like hand postures much earlier and more frequently than previously considered. Authors: Matthew M. Skinner, Nicholas B. Stephens, Zewdi J. Tsegai, Alexandra C. Foote, N. Huynh Nguyen, Thomas Gross, Dieter H. Pahr, Jean-Jacques Hublin, Tracy L. Kivell

Distinct types of CD4+ T cells protect the host against different classes of pathogens. However, it is unclear whether a given pathogen induces a single type of polarized T cell. By combining antigenic stimulation and T cell receptor deep sequencing, we found that human pathogen- and vaccine-specific T helper 1 (TH1), TH2, and TH17 memory cells have different frequencies but comparable diversity and comprise not only clones polarized toward a single fate, but also clones whose progeny have acquired multiple fates. Single naïve T cells primed by a pathogen in vitro could also give rise to multiple fates. Our results unravel an unexpected degree of interclonal and intraclonal functional heterogeneity of the human T cell response and suggest that polarized responses result from preferential expansion rather than priming. Authors: Simone Becattini, Daniela Latorre, Federico Mele, Mathilde Foglierini, Corinne De Gregorio, Antonino Cassotta, Blanca Fernandez, Sander Kelderman, Ton N. Schumacher, Davide Corti, Antonio Lanzavecchia, Federica Sallusto

The Large Magellanic Cloud, a satellite galaxy of the Milky Way, has been observed with the High Energy Stereoscopic System (H.E.S.S.) above an energy of 100 billion electron volts for a deep exposure of 210 hours. Three sources of different types were detected: the pulsar wind nebula of the most energetic pulsar known, N 157B; the radio-loud supernova remnant N 132D; and the largest nonthermal x-ray shell, the superbubble 30 Dor C. The unique object SN 1987A is, unexpectedly, not detected, which constrains the theoretical framework of particle acceleration in very young supernova remnants. These detections reveal the most energetic tip of a γ-ray source population in an external galaxy and provide via 30 Dor C the unambiguous detection of γ-ray emission from a superbubble. Author:

The deuterium-to-hydrogen (D/H) ratio in strongly bound water or hydroxyl groups in ancient martian clays retains the imprint of the water of formation of these minerals. Curiosity’s Sample Analysis at Mars (SAM) experiment measured thermally evolved water and hydrogen gas released between 550° and 950°C from samples of Hesperian-era Gale crater smectite to determine this isotope ratio. The D/H value is 3.0 (±0.2) times the ratio in standard mean ocean water. The D/H ratio in this ~3-billion-year-old mudstone, which is half that of the present martian atmosphere but substantially higher than that expected in very early Mars, indicates an extended history of hydrogen escape and desiccation of the planet. Authors: P. R. Mahaffy, C. R. Webster, J. C. Stern, A. E. Brunner, S. K. Atreya, P. G. Conrad, S. Domagal-Goldman, J. L. Eigenbrode, G. J. Flesch, L. E. Christensen, H. B. Franz, C. Freissinet, D. P. Glavin, J. P. Grotzinger, J. H. Jones, L. A. Leshin, C. Malespin, A. C. McAdam, D. W. Ming, R. Navarro-Gonzalez, P. B. Niles, T. Owen, A. A. Pavlov, A. Steele, M. G. Trainer, K. H. Williford, J. J. Wray,

Reports of plumes or patches of methane in the martian atmosphere that vary over monthly time scales have defied explanation to date. From in situ measurements made over a 20-month period by the tunable laser spectrometer of the Sample Analysis at Mars instrument suite on Curiosity at Gale crater, we report detection of background levels of atmospheric methane of mean value 0.69 ± 0.25 parts per billion by volume (ppbv) at the 95% confidence interval (CI). This abundance is lower than model estimates of ultraviolet degradation of accreted interplanetary dust particles or carbonaceous chondrite material. Additionally, in four sequential measurements spanning a 60-sol period (where 1 sol is a martian day), we observed elevated levels of methane of 7.2 ± 2.1 ppbv (95% CI), implying that Mars is episodically producing methane from an additional unknown source. Authors: Christopher R. Webster, Paul R. Mahaffy, Sushil K. Atreya, Gregory J. Flesch, Michael A. Mischna, Pierre-Yves Meslin, Kenneth A. Farley, Pamela G. Conrad, Lance E. Christensen, Alexander A. Pavlov, Javier Martín-Torres, María-Paz Zorzano, Timothy H. McConnochie, Tobias Owen, Jennifer L. Eigenbrode, Daniel P. Glavin, Andrew Steele, Charles A. Malespin, P. Douglas Archer, Brad Sutter, Patrice Coll, Caroline Freissinet, Christopher P. McKay, John E. Moores, Susanne P. Schwenzer, John C. Bridges, Rafael Navarro-Gonzalez, Ralf Gellert, Mark T. Lemmon,

Deep inside planets, extreme density, pressure, and temperature strongly modify the properties of the constituent materials. In particular, how much heat solids can sustain before melting under pressure is key to determining a planet’s internal structure and evolution. We report laser-driven shock experiments on fused silica, α-quartz, and stishovite yielding equation-of-state and electronic conductivity data at unprecedented conditions and showing that the melting temperature of SiO2 rises to 8300 K at a pressure of 500 gigapascals, comparable to the core-mantle boundary conditions for a 5–Earth mass super-Earth. We show that mantle silicates and core metal have comparable melting temperatures above 500 to 700 gigapascals, which could favor long-lived magma oceans for large terrestrial planets with implications for planetary magnetic-field generation in silicate magma layers deep inside such planets. Authors: M. Millot, N. Dubrovinskaia, A. Černok, S. Blaha, L. Dubrovinsky, D. G. Braun, P. M. Celliers, G. W. Collins, J. H. Eggert, R. Jeanloz

Crystalline materials that combine electrical polarization and magnetization could be advantageous in applications such as information storage, but these properties are usually considered to have incompatible chemical bonding and electronic requirements. Recent theoretical work on perovskite materials suggested a route for combining both properties. We used crystal chemistry to engineer specific atomic displacements in a layered perovskite, (CaySr1–y)1.15Tb1.85Fe2O7, that change its symmetry and simultaneously generate electrical polarization and magnetization above room temperature. The two resulting properties are magnetoelectrically coupled as they arise from the same displacements. Authors: Michael J. Pitcher, Pranab Mandal, Matthew S. Dyer, Jonathan Alaria, Pavel Borisov, Hongjun Niu, John B. Claridge, Matthew J. Rosseinsky

We propose a general strategy to synthesize largely unexplored soluble chalcogenidometallates of cadmium, lead, and bismuth. These compounds can be used as “solders” for semiconductors widely used in photovoltaics and thermoelectrics. The addition of solder helped to bond crystal surfaces and link nano- or mesoscale particles together. For example, CdSe nanocrystals with Na2Cd2Se3 solder was used as a soluble precursor for CdSe films with electron mobilities exceeding 300 square centimeters per volt-second. CdTe, PbTe, and Bi2Te3 powders were molded into various shapes in the presence of a small additive of composition-matched chalcogenidometallate or chalcogel, thus opening new design spaces for semiconductor technologies. Authors: Dmitriy S. Dolzhnikov, Hao Zhang, Jaeyoung Jang, Jae Sung Son, Matthew G. Panthani, Tomohiro Shibata, Soma Chattopadhyay, Dmitri V. Talapin

The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites. Authors: Judith Straimer, Nina F. Gnädig, Benoit Witkowski, Chanaki Amaratunga, Valentine Duru, Arba Pramundita Ramadani, Mélanie Dacheux, Nimol Khim, Lei Zhang, Stephen Lam, Philip D. Gregory, Fyodor D. Urnov, Odile Mercereau-Puijalon, Françoise Benoit-Vical, Rick M. Fairhurst, Didier Ménard, David A. Fidock

Artemisinin resistance in Plasmodium falciparum threatens global efforts to control and eliminate malaria. Polymorphisms in the kelch domain–carrying protein K13 are associated with artemisinin resistance, but the underlying molecular mechanisms are unknown. We analyzed the in vivo transcriptomes of 1043 P. falciparum isolates from patients with acute malaria and found that artemisinin resistance is associated with increased expression of unfolded protein response (UPR) pathways involving the major PROSC and TRiC chaperone complexes. Artemisinin-resistant parasites also exhibit decelerated progression through the first part of the asexual intraerythrocytic development cycle. These findings suggest that artemisinin-resistant parasites remain in a state of decelerated development at the young ring stage, whereas their up-regulated UPR pathways mitigate protein damage caused by artemisinin. The expression profiles of UPR-related genes also associate with the geographical origin of parasite isolates, further suggesting their role in emerging artemisinin resistance in the Greater Mekong Subregion. Authors: Sachel Mok, Elizabeth A. Ashley, Pedro E. Ferreira, Lei Zhu, Zhaoting Lin, Tomas Yeo, Kesinee Chotivanich, Mallika Imwong, Sasithon Pukrittayakamee, Mehul Dhorda, Chea Nguon, Pharath Lim, Chanaki Amaratunga, Seila Suon, Tran Tinh Hien, Ye Htut, M. Abul Faiz, Marie A. Onyamboko, Mayfong Mayxay, Paul N. Newton, Rupam Tripura, Charles J. Woodrow, Olivo Miotto, Dominic P. Kwiatkowski, François Nosten, Nicholas P. J. Day, Peter R. Preiser, Nicholas J. White, Arjen M. Dondorp, Rick M. Fairhurst, Zbynek Bozdech

Recovery from infection is not always complete, and mild chronic infection may persist. Although the direct costs of such infections are apparently small, the potential for any long-term effects on Darwinian fitness is poorly understood. In a wild population of great reed warblers, we found that low-level chronic malaria infection reduced life span as well as the lifetime number and quality of offspring. These delayed fitness effects of malaria appear to be mediated by telomere degradation, a result supported by controlled infection experiments on birds in captivity. The results of this study imply that chronic infection may be causing a series of small adverse effects that accumulate and eventually impair phenotypic quality and Darwinian fitness. Authors: M. Asghar, D. Hasselquist, B. Hansson, P. Zehtindjiev, H. Westerdahl, S. Bensch

The 26S proteasome is a key player in eukaryotic protein quality control and in the regulation of numerous cellular processes. Here, we describe quantitative in situ structural studies of this highly dynamic molecular machine in intact hippocampal neurons. We used electron cryotomography with the Volta phase plate, which allowed high fidelity and nanometer precision localization of 26S proteasomes. We undertook a molecular census of single- and double-capped proteasomes and assessed the conformational states of individual complexes. Under the conditions of the experiment—that is, in the absence of proteotoxic stress—only 20% of the 26S proteasomes were engaged in substrate processing. The remainder was in the substrate-accepting ground state. These findings suggest that in the absence of stress, the capacity of the proteasome system is not fully used. Authors: Shoh Asano, Yoshiyuki Fukuda, Florian Beck, Antje Aufderheide, Friedrich Förster, Radostin Danev, Wolfgang Baumeister

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America's medical residency training programs have come a long way since the late nineteenth century, but changes in the nature of hospital care have some questioning how best to facilitate high-quality care and high-quality education. Cynthia Whitehead welcomes a thorough appraisal of U.S. residency education in a review of Let Me Heal: The Opportunity to Preserve Excellence in American Medicine.

Authors: P. Sriramarao, Michael P. Murtaugh, Kavita Berger, Dominic Travis, Shaun Kennedy, Clifford J. Steer, Carol Cardona

Marine defaunation, or human-caused animal loss in the oceans, emerged forcefully only hundreds of years ago, whereas terrestrial defaunation has been occurring far longer. Though humans have caused few global marine extinctions, we have profoundly affected marine wildlife, altering the functioning and provisioning of services in every ocean. Current ocean trends, coupled with terrestrial defaunation lessons, suggest that marine defaunation rates will rapidly intensify as human use of the oceans industrializes. Though protected areas are a powerful tool to harness ocean productivity, especially when designed with future climate in mind, additional management strategies will be required. Overall, habitat degradation is likely to intensify as a major driver of marine wildlife loss. Proactive intervention can avert a marine defaunation disaster of the magnitude observed on land. Authors: Douglas J. McCauley, Malin L. Pinsky, Stephen R. Palumbi, James A. Estes, Francis H. Joyce, Robert R. Warner

Our understanding of when and how humans adapted to living on the Tibetan Plateau at altitudes above 2000 to 3000 meters has been constrained by a paucity of archaeological data. Here we report data sets from the northeastern Tibetan Plateau indicating that the first villages were established only by 5200 calendar years before the present (cal yr B.P.). Using these data, we tested the hypothesis that a novel agropastoral economy facilitated year-round living at higher altitudes since 3600 cal yr B.P. This successful subsistence strategy facilitated the adaptation of farmers-herders to the challenges of global temperature decline during the late Holocene. Authors: F. H. Chen, G. H. Dong, D. J. Zhang, X. Y. Liu, X. Jia, C. B. An, M. M. Ma, Y. W. Xie, L. Barton, X. Y. Ren, Z. J. Zhao, X. H. Wu, M. K. Jones

The physiological and biomechanical requirements of flight at high altitude have been the subject of much interest. Here, we uncover a steep relation between heart rate and wingbeat frequency (raised to the exponent 3.5) and estimated metabolic power and wingbeat frequency (exponent 7) of migratory bar-headed geese. Flight costs increase more rapidly than anticipated as air density declines, which overturns prevailing expectations that this species should maintain high-altitude flight when traversing the Himalayas. Instead, a “roller coaster” strategy, of tracking the underlying terrain and discarding large altitude gains only to recoup them later in the flight with occasional benefits from orographic lift, is shown to be energetically advantageous for flights over the Himalayas. Authors: C. M. Bishop, R. J. Spivey, L. A. Hawkes, N. Batbayar, B. Chua, P. B. Frappell, W. K. Milsom, T. Natsagdorj, S. H. Newman, G. R. Scott, J. Y. Takekawa, M. Wikelski, P. J. Butler