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This work demonstrates the application of a 3D culture system - Cells-in-Gels-in-Paper (CiGiP) - in evaluating the metabolic response of lung cancer cells to ionizing radiation. The 3D tissue-like construct - prepared by stacking multiple sheets of paper containing cell-embedded hydrogels - generates a gradient of oxygen and nutrients that decreases monotonically in the stack. Separating the layers of the stack after exposure enabled analysis of the cellular response to radiation as a function of oxygen and nutrient availability; this availability is dictated by the distance between the cells and the source of oxygenated medium. As the distance between the cells and source of oxygenated media increased, cells show increased levels of hypoxia-inducible factor 1-alpha, decreased proliferation, and reduced sensitivity to ionizing radiation. Each of these cellular responses are characteristic of cancer cells observed in solid tumors. With this setup we were able to differentiate three isogenic variants of A549 cells based on their metabolic radiosensitivity; these three variants have known differences in their metastatic behavior in vivo. This system can, therefore, capture some aspects of radiosensitivity of populations of cancer cells related to mass-transport phenomenon, carry out systematic studies of radiation response in vitro that decouple effects from migration and proliferation of cells, and regulate the exposure of oxygen to subpopulations of cells in a tissue-like construct either before or after irradiation., Chemistry and Chemical Biology

This work describes a 3D, paper-based assay that can isolate subpopulations of cells based on their invasiveness (i.e., distance migrated in a hydrogel) in a gradient of concentration of oxygen (O2). Layers of paper impregnated with a cell-compatible hydrogel are stacked and placed in a plastic holder to form the invasion assay. Stacking the layers of paper assembles them into 3D tissue-like constructs of defined thickness and composition. The plastic holder ensures the layers of paper are in conformal contact; this geometry allows the cells to migrate between adjacent layers through the embedded hydrogel. In most assays, the stack comprises a single layer of paper containing mammalian cells suspended in a hydrogel, sandwiched between multiple layers of paper containing only hydrogel (into which the cells migrate). Cells in the stack consume and produce small molecules; these molecules diffuse throughout the stack to generate gradients both in the stack, and between the stack and the bulk culture medium. Placing the cell-containing layer in different positions of the stack, or modifying the permeability of the holder to oxygen or proteins, alters the profile of the gradients within the stack. Physically separating the layers after culture isolates subpopulations of cells that migrated different distances, and enables their subsequent analysis or culture. Using this system, three independent cell lines derived from A549 cancer cells are shown to produce distinguishable migration behavior in a gradient of oxygen. This result is the first experimental demonstration that oxygen acts as a chemoattractant for cancer cells., Chemistry and Chemical Biology

This paper demonstrates a new soft structure that uses a meso- or macro-scale elastic instability to generate a shape-memory effect similar to that exhibited by a ferroelastic material. It demonstrates the phase transitions, state switching, and shape-memory effects in this system, both in experiment and in simulation. The new class of materials described in the paper is potentially useful, since it comprises what are effectively ‘‘shape-memory alloys’’ of arbitrarily low modulus and arbitrarily large remnant strain. The reproduction of properties of materials usually associated with atomic- or molecular-level changes in structure using meso-scale structural opens the door to development of new, soft materials with new properties and functions., Chemistry and Chemical Biology

Indicator species (IS) are used to monitor environmental changes, assess the efficacy of management, and provide warning signals for impending ecological shifts. Though widely adopted in recent years by ecologists, conservation biologists, and environmental practitioners, the use of IS has been criticized for several reasons, notably the lack of justification behind the choice of any given indicator. In this review, we assess how ecologists have selected, used, and evaluated the performance of the indicator species. We reviewed all articles published in Ecological Indicators (EI) between January 2001 and December 2014, focusing on the number of indicators used (one or more); common taxa employed; terminology, application, and rationale behind selection criteria; and performance assessment methods. Over the last 14 years, 1914 scientific papers were published in EI, describing studies conducted in 53 countries on six continents; of these, 817 (43%) used biological organisms as indicators. Terms used to describe organisms in IS research included “ecological index”, “environmental index”, “indicator species”, “bioindicator”, and “biomonitor,” but these and other terms often were not clearly defined. Twenty percent of IS publications used only a single species as an indicator; the remainder used groups of species as indicators. Nearly 50% of the taxa used as indicators were animals, 70% of which were invertebrates. The most common applications behind the use of IS were to: monitor ecosystem or environmental health and integrity (42%); assess habitat restoration (18%); and assess effects of pollution and contamination (18%). Indicators were chosen most frequently based on previously cited research (40%), local abundance (5%), ecological significance and/or conservation status (13%), or a combination of two or more of these reasons (25%). Surprisingly, 17% of the reviewed papers cited no clear justification for their choice of indicator. The vast majority (99%) of publications used statistical methods to assess the performance of the selected indicators. This review not only improves our understanding of the current uses and applications of IS, but will also inform practitioners about how to better select and evaluate ecological indicators when conducting future IS research., Organismic and Evolutionary Biology

The paper considers opportunities to reduce emissions of CO2 through increases in commitments to wind in a representative US power market. A model is applied to simulate market operations for different wind levels focusing on implications of the reduction in clearing prices arising due to increasing inputs of zero marginal cost power from wind, a dilemma referred to as the missing money problem. The resulting decrease in income poses problems for existing thermal and nuclear generating systems, at the same time making investments in wind uneconomic in the absence offsetting policy interventions. Two options are considered to subsidize cost: an investment credit (IC) or a subsidy on production (PC). The dilemma could be addressed also with a carbon tax targeted to increase income. It is assumed that the cost associated with the IC and PC options should be borne by the consumer, offsetting benefits from lower wholesale prices. It is assumed further that income from the carbon tax should be rebated to the consumer offsetting related increases in clearing prices. IC and PC options offer opportunities to reduce emissions at low or even negative net costs to the consumer. Higher costs are associated with the option of a carbon tax., Other Research Unit

This paper studies a model of intermediated exchange with liquidity-constrained traders. Intermediaries are embedded in a trading network and their financial capacities are private information. We characterize our model’s monotone, pure-strategy equilibrium. Agents earn positive intermediation rents in equilibrium. An experimental investigation supports the model’s baseline predictions concerning agents’ strategies, price dynamics, and the division of surplus. While private financial constraints inject uncertainty into the trading environment, our experiment suggests they are also a behavioral speed-bump, preventing traders from experiencing excessive losses due to overbidding.

The development of reproducible folding in the gyrencephalic cerebral cortex is a topic of great interest to neuroscientists. In a recent paper in Cell, del Toro et al. (2017) show that changing the adhesive properties of neurons in the normally lissencephalic mouse cortex leads to the formation of stereotyped folding., Stem Cell and Regenerative Biology

Elastomeric seals are essential to two great technological advances in oilfields: horizontal drilling and hydraulic fracturing. This paper describes a method to study elastomeric seals by using the pressure-extrusion curve (i.e., the relation between the drop of pressure across a seal and the volume of extrusion of the elastomer). Emphasis is placed on a common mode of failure found in oilfields: leak caused by a crack across the length of a long seal. We obtain an analytical solution of large elastic deformation, which is analogous to the Poiseuille flow of viscous liquids. We further obtain analytical expressions for the energy release rate of a crack and the critical pressure for the onset of its propagation. The theory predicts the pressure-extrusion curve using material parameters (elastic modulus, sliding stress, and fracture energy) and geometric parameters (thickness, length, and precompression). We fabricate seals of various parameters in transparent chambers on a desktop, and watch the seals extrude, slide, rupture and leak. The experimentally measured pressure-extrusion curves agree with theoretical predictions remarkably well., Engineering and Applied Sciences, Physics, Other Research Unit

The molecular linkage between neocortical projection neuron subtype and area development, which enables the establishment of functional areas by projection neuron populations appropriate for specific sensory and motor functions, is poorly understood. Here, we report that Ctip1 controls precision of neocortical development by regulating subtype identity in deep-layer projection neurons. Ctip1 is expressed by postmitotic callosal and corticothalamic projection neurons, but is excluded over embryonic development from corticospinal motor neurons, which instead express its close relative, Ctip2. Loss of Ctip1 function results in a striking bias in favor of subcerebral projection neuron development in sensory cortex at the expense of corticothalamic and deep-layer callosal development, while misexpression of Ctip1 in vivo represses subcerebral gene expression and projections. As we report in a paired paper, Ctip1 also controls acquisition of sensory area identity. Therefore, Ctip1 couples subtype and area specification, enabling specific functional areas to organize precise ratios of appropriate output projections., Stem Cell and Regenerative Biology

This paper describes the hardware and operations of the Neutrinos at the Main Injector (NuMI) beam at Fermilab. It elaborates on the design considerations for the beam as a whole and for individual elements. The most important design details of individual components are described. Beam monitoring systems and procedures, including the tuning and alignment of the beam and NuMI longterm performance, are also discussed., Physics

Development of shale gas resources is expected to play an important role in China's projected transition to a low-carbon energy future. The question arises whether the availability of water could limit this development. The paper considers a range of scenarios to define the demand for water needed to accommodate China's projected shale gas production through 2020. Based on data from the gas field at Fuling, the first large-scale shale gas field in China, it is concluded that the water intensity for shale gas development in China (water demand per unit lateral length) is likely to exceed that in the US by about 50%. Fuling field would require a total of 39.9–132.9 Mm3 of water to achieve full development of its shale gas, with well spacing assumed to vary between 300 and 1000 m. To achieve the 2020 production goal set by Sinopec, the key Chinese developer, water consumption is projected to peak at 7.22 Mm3 in 2018. Maximum water consumption would account for 1% and 3%, respectively, of the available water resource and annual water use in the Fuling district. To achieve China's nationwide shale gas production goal set for 2020, water consumption is projected to peak at 15.03 Mm3 in 2019 in a high-use scenario. It is concluded that supplies of water are adequate to meet demand in Fuling and most projected shale plays in China, with the exception of localized regions in the Tarim and Jungger Basins., Engineering and Applied Sciences

Urban intensity, in this paper, is measured by four related concepts: compactness, diversity, density, and connectivity. Together they lead to a single idea when considering spatial distributions potentially in a virtuous manner with regard to resource consumption, economic opportunity, social integration and environmental performance. The methodologies applied here included Moran's I, Shannon's index entropy, and accessibility isotimelines, which were then applied to real case scenarios in 20 towns in Zhejiang Province, selected based on their economic performances, population sizes, and geographical locations. Further inspection discovered that density, an outcome of urban form, is highly correlated to compactness, leading to its elimination. The results showed that among the varying spatial arrangements of urban activities, building footprints and infrastructural elements characterized by monocentric centers of use inscribed with well-defined and relatively uniform grids of streets and related networks, alongside of relatively integrated zones of use, seemed to perform best with regard to urban intensity. At the other end of the morphological spectrum, towns with sharp separations of uses and zones of development, often resulting in overall bifurcation of a town's spatial layout, performed less well. Also, linear forms for small towns were less favorable.

Coronary artery disease (CAD) has dominated mortality for most of the past century, not just in Europe and North America but worldwide. Treatments for CAD, both pharmaceutical and surgical, have become leading sectors of the healthcare economy. This paper focuses on the therapeutic landscape for CAD in the United States. We hope to add texture to the broader conversation of pharmaceuticalization explored in this issue by situating pharmaceutical therapies as just one element in the broader therapeutic terrain, alongside cardiac surgery and interventional cardiology. Patients with CAD must navigate a therapeutic landscape with three intersecting paths: lifestyle change, pharmaceuticals, and surgery. While pharmaceuticals are often seen as a quick fix, a way of avoiding more difficult lifestyle changes, it is surgery and angioplasty that promise patients the quickest fix of all. There also is another option, often overlooked by analysts but popular among physicians and patients: inaction. The U.S. context is often critiqued as a site of excessive treatment with respect to both drugs and procedures, and yet there is deep stratification within it – over-treatment in many populations and under-treatment in others. People who experience the serious risks of CAD do so in a racialized terrain of durable preoccupations with difference and unequal access to care. While the pharmaceuticalization literature disproportionately attends to lifestyle drugs, which some observers consider to be medically inappropriate or unnecessary, CAD does remain the leading cause of death. Thus, the stakes are high. Examination of the pharmaceuticalization of CAD in light of surgical treatments and racial disparities offers a window into the pervasiveness and persuasiveness of pharmaceuticals in an increasingly consumer-driven medicine, as well as the limits of their appeal and their reach., History of Science

This paper explores the menu of options for renormalizing public debt levels relative to nominal activity in the long run, should governments eventually decide to do so. Although debt ratios may need to rise further in some cases, a vision of longer-term options is key to weighing alternative medium-term stabilization strategies. Orthodox ones, the standard fare of officialdom, include enhancing growth, running primary budget surpluses, and privatizing government assets. Heterodox polices include restructuring debt contracts, generating unexpected inflation, taxing wealth, and repressing private finance. Advanced countries have relied far more on heterodox approaches than many observers choose to remember., Economics

Research consistently shows that college choice in an important predictor of college completion and labor market outcomes. These longer term implications of college choice, combined with suboptimal choices made by many low-income but high-achieving students, has sparked several large-scale initiatives to improve college choice. Strategically targeting those students most susceptible to making questionable decisions in the college-choice process remains challenging, as variation in college choice is largely unexplained by easily measurable socio-demographic characteristics. This paper explores the potential to improve upon existing models and, more generally, to better understand college choice by documenting the similarities in college enrollment patterns between younger and older siblings. To do so, we identify siblings in the millions of SAT test-takers between the 2004 and 2011 high school graduation cohorts. We find that younger siblings enroll in the same college as their older sibling 21.2 percent of the time. Also, conditional on their own SAT scores, we find that younger siblings whose older siblings enrolled in four-year colleges and the most selective colleges are 17.4 and 21.3 percentage points, respectively, more likely to themselves enroll in four-year and the most selective colleges. Overall, adding characteristics and enrollment decisions of older siblings to standard college choice models improves model fit and consequently, are valuable pieces of information for explanatory and predictive power., Economics

The concept of "exorbitant privilege" has received great attention from policy makers as well as academics worldwide. The idea originally referred to the willingness of foreigners to hold large quantities of US government debt at extremely low interest rates, due to the dollar's world reserve currency status. In recent years, the term exorbitant privilege has been expanded to explain why the US appears to be enjoying excess return from its external assets over liabilities across all asset classes, including foreign direct investment, equities and other forms of portfolio investment. In this paper, we give a brief review of the recent literature on exorbitant privilege, and then proceed to discuss exorbitant privilege in the context of another country, Japan, which has been the world's largest creditor nation for more than two decades. In contrast to the common perception that Japan has been a particularly poor international investor, we find that Japan enjoys exorbitant privilege in both the broad and narrow sense. Japan also earns higher expected returns from maturity transformation. Thus although the dollar is the reserve currency, the yen also has enjoyed a safe haven effect in the recent period., Economics