Showing papers in "Science in 2004"

Electric Field Effect in Atomically Thin Carbon Films

Abstract: We describe monocrystalline graphitic films, which are a few atoms thick but are nonetheless stable under ambient conditions, metallic, and of remarkably high quality. The films are found to be a two-dimensional semimetal with a tiny overlap between valence and conductance bands, and they exhibit a strong ambipolar electric field effect such that electrons and holes in concentrations up to 10 13 per square centimeter and with room-temperature mobilities of ∼10,000 square centimeters per volt-second can be induced by applying gate voltage.

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

Abstract: Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or

Neutrophil extracellular traps kill bacteria

Abstract: Neutrophils engulf and kill bacteria when their antimicrobial granules fuse with the phagosome. Here, we describe that, upon activation, neutrophils release granule proteins and chromatin that together form extracellular fibers that bind Gram-positive and -negative bacteria. These neutrophil extracellular traps (NETs) degrade virulence factors and kill bacteria. NETs are abundant in vivo in experimental dysentery and spontaneous human appendicitis, two examples of acute inflammation. NETs appear to be a form of innate response that binds microorganisms, prevents them from spreading, and ensures a high local concentration of antimicrobial agents to degrade virulence factors and kill bacteria.

Soil carbon sequestration impacts on global climate change and food security.

Abstract: :The carbon sink capacity of the world’s agricultural and degraded soils is 50 to 66% of the historic carbon loss of 42 to 78 gigatons of carbon. The rate of soil organic carbon sequestration with adoption of recommended technologies depends on soil texture and structure, rainfall, temperature, farming system, and soil management. Strategies to increase the soil carbon pool include soil restoration and woodland regeneration, no-till farming, cover crops, nutrient management, manuring and sludge application, improved grazing, water conservation and harvesting, efficient irrigation, agroforestry practices, and growing energy crops on spare lands. An increase of 1 ton of soil carbon pool of degraded cropland soils may increase crop yield by 20 to 40 kilograms per hectare (kg/ha) for wheat, 10 to 20 kg/ha for maize, and 0.5 to 1 kg/ha for cowpeas. As well as enhancing food security, carbon sequestration has the potential to offset fossilfuel emissions by 0.4 to 1.2 gigatons of carbon per year, or 5 to 15% of the global fossil-fuel emissions.

Neuronal Oscillations in Cortical Networks

Abstract: Clocks tick, bridges and skyscrapers vibrate, neuronal networks oscillate. Are neuronal oscillations an inevitable by-product, similar to bridge vibrations, or an essential part of the brain’s design? Mammalian cortical neurons form behavior-dependent oscillating networks of various sizes, which span five orders of magnitude in frequency. These oscillations are phylogenetically preserved, suggesting that they are functionally relevant. Recent findings indicate that network oscillations bias input selection, temporally link neurons into assemblies, and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation and long-term consolidation of information.

In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.

Abstract: MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy. Here, we identify potent and selective small-molecule antagonists of MDM2 and confirm their mode of action through the crystal structures of complexes. These compounds bind MDM2 in the p53-binding pocket and activate the p53 pathway in cancer cells, leading to cell cycle arrest, apoptosis, and growth inhibition of human tumor xenografts in nude mice.

Environmental Genome Shotgun Sequencing of the Sargasso Sea

Abstract: We have applied “whole-genome shotgun sequencing” to microbial populations collected en masse on tangential flow and impact filters from seawater samples collected from the Sargasso Sea near Bermuda. A total of 1.045 billion base pairs of nonredundant sequence was generated, annotated, and analyzed to elucidate the gene content, diversity, and relative abundance of the organisms within these environmental samples. These data are estimated to derive from at least 1800 genomic species based on sequence relatedness, including 148 previously unknown bacterial phylotypes. We have identified over 1.2 million previously unknown genes represented in these samples, including more than 782 new rhodopsin-like photoreceptors. Variation in species present and stoichiometry suggests substantial oceanic microbial diversity. Microorganisms are responsible for most of the biogeochemical cycles that shape the environment of Earth and its oceans. Yet, these organisms are the least well understood on Earth, as the ability to study and understand the metabolic potential of microorganisms has been hampered by the inability to generate pure cultures. Recent studies have begun to explore environ

Sustainable Hydrogen Production

Abstract: Identifying and building a sustainable energy system are perhaps two of the most critical issues that today's society must address. Replacing our current energy carrier mix with a sustainable fuel is one of the key pieces in that system. Hydrogen as an energy carrier, primarily derived from water, can address issues of sustainability, environmental emissions, and energy security. Issues relating to hydrogen production pathways are addressed here. Future energy systems require money and energy to build. Given that the United States has a finite supply of both, hard decisions must be made about the path forward, and this path must be followed with a sustained and focused effort.

Drug Delivery Systems: Entering the Mainstream

Abstract: Drug delivery systems (DDS) such as lipid- or polymer-based nanoparticles can be designed to improve the pharmacological and therapeutic properties of drugs administered parenterally. Many of the early problems that hindered the clinical applications of particulate DDS have been overcome, with several DDS formulations of anticancer and antifungal drugs now approved for clinical use. Furthermore, there is considerable interest in exploiting the advantages of DDS for in vivo delivery of new drugs derived from proteomics or genomics research and for their use in ligand-targeted therapeutics.

Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization

Abstract: Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here we report that hepcidin bound to ferroportin in tissue culture cells. After binding, ferroportin was internalized and degraded, leading to decreased export of cellular iron. The posttranslational regulation of ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of ferroportin on the cell surface.

Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8

Abstract: Double-stranded ribonucleic acid (dsRNA) serves as a danger signal associated with viral infection and leads to stimulation of innate immune cells. In contrast, the immunostimulatory potential of single-stranded RNA (ssRNA) is poorly understood and innate immune receptors for ssRNA are unknown. We report that guanosine (G)- and uridine (U)-rich ssRNA oligonucleotides derived from human immunodeficiency virus-1 (HIV-1) stimulate dendritic cells (DC) and macrophages to secrete interferon-alpha and proinflammatory, as well as regulatory, cytokines. By using Toll-like receptor (TLR)-deficient mice and genetic complementation, we show that murine TLR7 and human TLR8 mediate species-specific recognition of GU-rich ssRNA. These data suggest that ssRNA represents a physiological ligand for TLR7 and TLR8.

Metamaterials and negative refractive index.

Abstract: Recently, artificially constructed metamaterials have become of considerable interest, because these materials can exhibit electromagnetic characteristics unlike those of any conventional materials. Artificial magnetism and negative refractive index are two specific types of behavior that have been demonstrated over the past few years, illustrating the new physics and new applications possible when we expand our view as to what constitutes a material. In this review, we describe recent advances in metamaterials research and discuss the potential that these materials may hold for realizing new and seemingly exotic electromagnetic phenomena.

Status and Trends of Amphibian Declines and Extinctions Worldwide

Abstract: The first global assessment of amphibians provides new context for the well-publicized phenomenon of amphibian declines. Amphibians are more threatened and are declining more rapidly than either birds or mammals. Although many declines are due to habitat loss and overutilization, other, unidentified processes threaten 48% of rapidly declining species and are driving species most quickly to extinction. Declines are nonrandom in terms of species' ecological preferences, geographic ranges, and taxonomic associations and are most prevalent among Neotropical montane, stream-associated species. The lack of conservation remedies for these poorly understood declines means that hundreds of amphibian species now face extinction.

Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

Abstract: Obesity contributes to the development of type 2 diabetes, but the underlying mechanisms are poorly understood. Using cell culture and mouse models, we show that obesity causes endoplasmic reticulum (ER) stress. This stress in turn leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1). Mice deficient in X-box-binding protein-1 (XBP-1), a transcription factor that modulates the ER stress response, develop insulin resistance. These findings demonstrate that ER stress is a central feature of peripheral insulin resistance and type 2 diabetes at the molecular, cellular, and organismal levels. Pharmacologic manipulation of this pathway may offer novel opportunities for treating these common diseases.

Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

Abstract: Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.

Empathy for Pain Involves the Affective but not Sensory Components of Pain

Abstract: Our ability to have an experience of another's pain is characteristic of empathy. Using functional imaging, we assessed brain activity while volunteers experienced a painful stimulus and compared it to that elicited when they observed a signal indicating that their loved one--present in the same room--was receiving a similar pain stimulus. Bilateral anterior insula (AI), rostral anterior cingulate cortex (ACC), brainstem, and cerebellum were activated when subjects received pain and also by a signal that a loved one experienced pain. AI and ACC activation correlated with individual empathy scores. Activity in the posterior insula/secondary somatosensory cortex, the sensorimotor cortex (SI/MI), and the caudal ACC was specific to receiving pain. Thus, a neural response in AI and rostral ACC, activated in common for "self" and "other" conditions, suggests that the neural substrate for empathic experience does not involve the entire "pain matrix." We conclude that only that part of the pain network associated with its affective qualities, but not its sensory qualities, mediates empathy.

Ecological linkages between aboveground and belowground biota.

Abstract: All terrestrial ecosystems consist of aboveground and belowground components that interact to influence community- and ecosystem-level processes and properties. Here we show how these components are closely interlinked at the community level, reinforced by a greater degree of specificity between plants and soil organisms than has been previously supposed. As such, aboveground and belowground communities can be powerful mutual drivers, with both positive and negative feedbacks. A combined aboveground-belowground approach to community and ecosystem ecology is enhancing our understanding of the regulation and functional significance of biodiversity and of the environmental impacts of human-induced global change phenomena.

High frequency of mutations of the PIK3CA gene in human cancers

Abstract: Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate signaling pathways important for neoplasia, including cell proliferation, adhesion, survival, and motility ([ 1 ][1]–[ 3 ][2]). To determine if PI3Ks are genetically altered in tumorigenesis, we sequenced PI3K genes in human

MicroRNAs Modulate Hematopoietic Lineage Differentiation

Abstract: MicroRNAs (miRNAs) are an abundant class of ∼22-nucleotide regulatory RNAs found in plants and animals. Some miRNAs of plants, Caenorhabditis elegans, and Drosophila play important gene-regulatory roles during development by pairing to target mRNAs to specify posttranscriptional repression of these messages. We identify three miRNAs that are specifically expressed in hematopoietic cells and show that their expression is dynamically regulated during early hematopoiesis and lineage commitment. One of these miRNAs, miR-181, was preferentially expressed in the B-lymphoid cells of mouse bone marrow, and its ectopic expression in hematopoietic stem/progenitor cells led to an increased fraction of B-lineage cells in both tissue-culture differentiation assays and adult mice. Our results indicate that microRNAs are components of the molecular circuitry that controls mouse hematopoiesis and suggest that other microRNAs have similar regulatory roles during other facets of vertebrate development.

The Pathophysiology of Mitochondrial Cell Death

Abstract: In the mitochondrial pathway of apoptosis, caspase activation is closely linked to mitochondrial outer membrane permeabilization (MOMP). Numerous pro-apoptotic signal-transducing molecules and pathological stimuli converge on mitochondria to induce MOMP. The local regulation and execution of MOMP involve proteins from the Bcl-2 family, mitochondrial lipids, proteins that regulate bioenergetic metabolite flux, and putative components of the permeability transition pore. MOMP is lethal because it results in the release of caspase-activating molecules and caspase-independent death effectors, metabolic failure in the mitochondria, or both. Drugs designed to suppress excessive MOMP may avoid pathological cell death, and the therapeutic induction of MOMP may restore apoptosis in cancer cells in which it is disabled. The general rules governing the pathophysiology of MOMP and controversial issues regarding its regulation are discussed.

Architecture of the Photosynthetic Oxygen-Evolving Center

Abstract: Photosynthesis uses light energy to drive the oxidation of water at an oxygen-evolving catalytic site within photosystem II (PSII). We report the structure of PSII of the cyanobacterium Thermosynechococcus elongatus at 3.5 angstrom resolution. We have assigned most of the amino acid residues of this 650-kilodalton dimeric multisubunit complex and refined the structure to reveal its molecular architecture. Consequently, we are able to describe details of the binding sites for cofactors and propose a structure of the oxygen-evolving center (OEC). The data strongly suggest that the OEC contains a cubane-like Mn 3 CaO 4 cluster linked to a fourth Mn by a mono-μ-oxo bridge. The details of the surrounding coordination sphere of the metal cluster and the implications for a possible oxygen-evolving mechanism are discussed.

Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1

Abstract: Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6) Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6 We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress These data provide a direct molecular link between mitochondria and the pathogenesis of PD

More Intense, More Frequent, and Longer Lasting Heat Waves in the 21st Century

Abstract: A global coupled climate model shows that there is a distinct geographic pattern to future changes in heat waves. Model results for areas of Europe and North America, associated with the severe heat waves in Chicago in 1995 and Paris in 2003, show that future heat waves in these areas will become more intense, more frequent, and longer lasting in the second half of the 21st century. Observations and the model show that present-day heat waves over Europe and North America coincide with a specific atmospheric circulation pattern that is intensified by ongoing increases in greenhouse gases, indicating that it will produce more severe heat waves in those regions in the future.

The oceanic sink for anthropogenic CO2.

Abstract: Using inorganic carbon measurements from an international survey effort in the 1990s and a tracer-based separation technique, we estimate a global oceanic anthropogenic carbon dioxide (CO2) sink for the period from 1800 to 1994 of 118 19 petagrams of carbon. The oceanic sink accounts for48% of the total fossil-fuel and cement-manufacturing emissions, implying that the terrestrial biosphere was a net source of CO 2 to the atmosphere of about 39 28 petagrams of carbon for this period. The current fraction of total anthropogenic CO2 emissions stored in the ocean appears to be about one-third of the long-term potential. Since the beginning of the industrial period in the late 18th century, i.e., over the anthropocene (1), humankind has emitted large quantities of CO2 into the atmosphere, mainly as a result of fossil-fuel burning, but also because of land-use practices, e.g., deforestation (2). Measurements and reconstructions of the atmospheric CO2 history reveal, however, that less than half of these emissions remain in the atmosphere (3). The anthropogenic CO2 that did not accumulate in the atmosphere must have been taken up by the ocean, by the land biosphere, or by a combination of both. The relative roles of the ocean and land biosphere as sinks for anthropogenic CO2 over the anthropocene are currently not known. Although the anthropogenic CO2 budget for the past two decades, i.e., the 1980s and 1990s, has been investigated in detail (3), the estimates of the ocean sink have not been based on direct measurements of changes in the oceanic inventory of dissolved inorganic carbon (DIC). Recognizing the need to constrain the oceanic uptake, transport, and storage of anthropogenic CO 2 for the anthropocene and to provide a baseline for future estimates of oceanic CO 2 uptake, two international ocean research programs, the World Ocean Circulation Experiment (WOCE) and the Joint Global Ocean Flux Study (JGOFS), jointly conducted a comprehensive survey of inorganic carbon distributions in the global ocean in the 1990s (4). After completion of the U.S. field program in 1998, a 5-year effort was begun to compile and rigorously quality-control the U.S. and international data sets, in

Transparent, Conductive Carbon Nanotube Films

Abstract: We describe a simple process for the fabrication of ultrathin, transparent, optically homogeneous, electrically conducting films of pure single-walled carbon nanotubes and the transfer of those films to various substrates. For equivalent sheet resistance, the films exhibit optical transmittance comparable to that of commercial indium tin oxide in the visible spectrum, but far superior transmittance in the technologically relevant 2- to 5-micrometer infrared spectral band. These characteristics indicate broad applicability of the films for electrical coupling in photonic devices. In an example application, the films are used to construct an electric field-activated optical modulator, which constitutes an optical analog to the nanotube-based field effect transistor.

Formation of hollow nanocrystals through the nanoscale Kirkendall effect

Abstract: Hollow nanocrystals can be synthesized through a mechanism analogous to the Kirkendall Effect, in which pores form because of the difference in diffusion rates between two components in a diffusion couple. Starting with cobalt nanocrystals, we show that their reaction in solution with oxygen and either sulfur or selenium leads to the formation of hollow nanocrystals of the resulting oxide and chalcogenides. This process provides a general route to the synthesis of hollow nanostructures of a large number of compounds. A simple extension of the process yielded platinum-cobalt oxide yolk-shell nanostructures, which may serve as nanoscale reactors in catalytic applications.

Stabilization Wedges: Solving the Climate Problem for the Next 50 Years with Current Technologies

Abstract: Humanity already possesses the fundamental scientific, technical, and industrial know-how to solve the carbon and climate problem for the next half-century. A portfolio of technologies now exists to meet the world’s energy needs over the next 50years and limit atmospheric CO 2 to a trajectory that avoids a doubling of the preindustrial concentration. Every element in this portfolio has passed beyond the laboratory bench and demonstration project; many are already implemented somewhere at full industrial scale. Although no element is a credible candidate for doing the entire job (or even half the job) by itself, the portfolio as a whole is large enough that not every element has to be used.

Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase

Abstract: The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.

Mass Spectrometry Sampling Under Ambient Conditions with Desorption Electrospray Ionization

Abstract: A new method of desorption ionization is described and applied to the ionization of various compounds, including peptides and proteins present on metal, polymer, and mineral surfaces. Desorption electrospray ionization (DESI) is carried out by directing electrosprayed charged droplets and ions of solvent onto the surface to be analyzed. The impact of the charged particles on the surface produces gaseous ions of material originally present on the surface. The resulting mass spectra are similar to normal ESI mass spectra in that they show mainly singly or multiply charged molecular ions of the analytes. The DESI phenomenon was observed both in the case of conductive and insulator surfaces and for compounds ranging from nonpolar small molecules such as lycopene, the alkaloid coniceine, and small drugs, through polar compounds such as peptides and proteins. Changes in the solution that is sprayed can be used to selectively ionize particular compounds, including those in biological matrices. In vivo analysis is demonstrated.

Anterior cingulate conflict monitoring and adjustments in control

Abstract: Conflict monitoring by the anterior cingulate cortex (ACC) has been posited to signal a need for greater cognitive control, producing neural and behavioral adjustments. However, the very occurrence of behavioral adjustments after conflict has been questioned, along with suggestions that there is no direct evidence of ACC conflict-related activity predicting subsequent neural or behavioral adjustments in control. Using the Stroop color-naming task and controlling for repetition effects, we demonstrate that ACC conflict-related activity predicts both greater prefrontal cortex activity and adjustments in behavior, supporting a role of ACC conflict monitoring in the engagement of cognitive control.