Astrophysics

8 typically slower than ϳ1 km s −1 ) might differ significantly from what is assumed by current modelling efforts 27 . The expected equation-of-state differences among small bodies (ice versus rock, for instance) presents another dimension of study; having recently adapted our code for massively parallel architectures (K. M. Olson and E.A, manuscript in preparation), we are now ready to perform a more comprehensive analysis.

Graphene sheets-one-atom-thick two-dimensional layers of sp 2 -bonded carbon-are predicted to have a range of unusual properties. Their thermal conductivity and mechanical stiffness may rival the remarkable in-plane values for graphite (,3,000 Wm 21 K 21 and 1,060 GPa, respectively); their fracture strength should be comparable to that of carbon nanotubes for similar types of defects 1-3 ; and recent studies have shown that individual graphene sheets have extraordinary electronic transport properties 4-8 . One possible route to harnessing these properties for applications would be to incorporate graphene sheets in a composite material. The manufacturing of such composites requires not only that graphene sheets be produced on a sufficient scale but that they also be incorporated, and homogeneously distributed, into various matrices. Graphite, inexpensive and available in large quantity, unfortunately does not readily exfoliate to yield individual graphene sheets. Here we present a general approach for the preparation of graphene-polymer composites via complete exfoliation of graphite 9 and molecular-level dispersion of individual, chemically modified graphene sheets within polymer hosts. A polystyrene-graphene composite formed by this route exhibits a percolation threshold 10 of ,0.1 volume per cent for room-temperature electrical conductivity, the lowest reported value for any carbon-based composite except for those involving carbon nanotubes 11 ; at only 1 volume per cent, this composite has a conductivity of ,0.1 S m 21 , sufficient for many electrical applications 12 . Our bottom-up chemical approach of tuning the graphene sheet properties provides a path to a broad new class of graphenebased materials and their use in a variety of applications.

Causal attribution of recent biological trends to climate change is complicated because non-climatic influences dominate local, short-term biological changes. Any underlying signal from climate change is likely to be revealed by analyses that seek systematic trends across diverse species and geographic regions; however, debates within the Intergovernmental Panel on Climate Change (IPCC) reveal several definitions of a 'systematic trend'. Here, we explore these differences, apply diverse analyses to more than 1,700 species, and show that recent biological trends match climate change predictions. Global meta-analyses documented significant range shifts averaging 6.1 km per decade towards the poles (or metres per decade upward), and significant mean advancement of spring events by 2.3 days per decade. We define a diagnostic fingerprint of temporal and spatial 'sign-switching' responses uniquely predicted by twentieth century climate trends. Among appropriate long-term/large-scale/multi-species data sets, this diagnostic fingerprint was found for 279 species. This suite of analyses generates 'very high confidence' (as laid down by the IPCC) that climate change is already affecting living systems.

The standard model of hot big bang cosmology requires initial conditions which are problematic in two ways: (1) the early universe is assumed to be highly homogeneous, in spite of the fact that separated regions were causally disconnected (horizon problem); and (2) the initial value of the Hubble constant must be fine tuned to extraordinary accuracy to produce a universe as flat (i.e., near critical mass density) as'the one we see today (flatness problem). These problems would disappear if, in its early history, the universe supercooled to temperatures 28 or more orders of magnitude below the critical temperature for some phase transition. A huge expansion factor would then result from a period of exponential growth, and the entropy of the universe would be multiplied by a huge factor when the latent heat is released. Such a scenario is completely natural in the context of grand unified models of elementary particle interactions. In such models, the supercooling is also relevant to the problem of monopole suppression. Unfortunately, the scenario seems to lead to some unacceptable consequences, so modifications must be sought.

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and ...

The long-standing challenge of designing and constructing new crystalline solid-state materials from molecular building blocks is just beginning to be addressed with success. A conceptual approach that requires the use of secondary building units to direct the assembly of ordered frameworks epitomizes this process: we call this approach reticular synthesis. This chemistry has yielded materials designed to have predetermined structures, compositions and properties. In particular, highly porous frameworks held together by strong metal-oxygen-carbon bonds and with exceptionally large surface area and capacity for gas storage have been prepared and their pore metrics systematically varied and functionalized. The deconstruction of diamond and lonsdaleite. a, diamond; b, lonsdaleite ('hexagonal diamond'). The units outlined in red are the natural tiles for these structures.

On activation, T cells undergo distinct developmental pathways, attaining specialized properties and effector functions. T-helper (T H ) cells are traditionally thought to differentiate into T H 1 and T H 2 cell subsets. T H 1 cells are necessary to clear intracellular pathogens and T H 2 cells are important for clearing extracellular organisms 1,2 . Recently, a subset of interleukin (IL)-17-producing T (T H 17) cells distinct from T H 1 or T H 2 cells has been described and shown to have a crucial role in the induction of autoimmune tissue injury 3-5 . In contrast, CD4 1 CD25 1 Foxp3 1 regulatory T (T reg ) cells inhibit autoimmunity and protect against tissue injury 6 . Transforming growth factor-b (TGF-b) is a critical differentiation factor for the generation of T reg cells 7 . Here we show, using mice with a reporter introduced into the endogenous Foxp3 locus, that IL-6, an acute phase protein induced during inflammation 8,9 , completely inhibits the generation of Foxp3 1 T reg cells induced by TGF-b. We also demonstrate that IL-23 is not the differentiation factor for the generation of T H 17 cells. Instead, IL-6 and TGF-b together induce the differentiation of pathogenic T H 17 cells from naive T cells. Our data demonstrate a dichotomy in the generation of pathogenic (T H 17) T cells that induce autoimmunity and regulatory (Foxp3 1 ) T cells that inhibit autoimmune tissue injury.

insight review articles NATURE | VOL 414 | 15 NOVEMBER 2001 | www.nature.com 353 E nergy can be stored in different forms: as mechanical energy (for example, potential energy or rotation energy of a flywheel); in an electric or magnetic field (capacitors and coils, respectively); as chemical energy of reactants and fuels (batteries, petrol or hydrogen); or as nuclear fuel (uranium or deuterium). Chemical and electric energy can be transmitted easily because they both involve electronic Coulomb interaction. Chemical energy is based on the energy of unpaired outer electrons (valence electrons) eager to be stabilized by electrons from other atoms. The hydrogen atom is most attractive because its electron (for charge neutrality) is accompanied by only one proton. Hydrogen thus has the best ratio of valence electrons to protons (and neutrons) of all the periodic table, and the energy gain per electron is very high.

All ecosystems are exposed to gradual changes in climate, nutrient loading, habitat fragmentation or biotic exploitation. Nature is usually assumed to respond to gradual change in a smooth way. However, studies on lakes, coral reefs, oceans, forests and arid lands have shown that smooth change can be interrupted by sudden drastic switches to a contrasting state. Although diverse events can trigger such shifts, recent studies show that a loss of resilience usually paves the way for a switch to an alternative state. This suggests that strategies for sustainable management of such ecosystems should focus on maintaining resilience.

Advances in the science and observation of climate change are providing a clearer understanding of the inherent variability of Earth's climate system and its likely response to human and natural influences. The implications of climate change for the environment and society will depend not only on the response of the Earth system to changes in radiative forcings, but also on how humankind responds through changes in technology, economies, lifestyle and policy. Extensive uncertainties exist in future forcings of and responses to climate change, necessitating the use of scenarios of the future to explore the potential consequences of different response options. To date, such scenarios have not adequately examined crucial possibilities, such as climate change mitigation and adaptation, and have relied on research processes that slowed the exchange of information among physical, biological and social scientists. Here we describe a new process for creating plausible scenarios to investigate some of the most challenging and important questions about climate change confronting the global community.

Despite their importance for urban planning [1], traffic forecasting [2], and the spread of biological [3, 4, 5] and mobile viruses [6], our understanding of the basic laws governing human motion remains limited thanks to the lack of tools to monitor the time resolved location of individuals. Here we study the trajectory of 100, 000 anonymized mobile phone users whose position is tracked for a six month period. We find that in contrast with the random trajectories predicted by the prevailing Lévy flight and random walk models [7], human trajectories show a high degree of temporal and spatial regularity, each individual being characterized by a time independent characteristic length scale and a significant probability to return to a few highly frequented locations. After correcting for differences in travel distances and the inherent anisotropy of each trajectory, the individual travel patterns collapse into a single spatial probability distribution, indicating that despite the diversity of their travel history, humans follow simple reproducible patterns. This inherent similarity in travel patterns could impact all phenomena driven by human mobility, from epidemic prevention to emergency response, urban planning and agent based modeling. Given the many unknown factors that influence a population's mobility patterns, ranging from means of transportation to job and family imposed restrictions and priorities, human trajectories are often approximated with various random walk or diffusion models [7, 8]. Indeed, early measurements on albatrosses, bumblebees, deer and monkeys [9, 10] and more recent ones on marine predators [11] suggested that animal trajectory is approximated by a Lévy flight [12, 13], a random walk whose step size ∆r follows a power-law distribution P (∆r) ∼ ∆r −(1+β) with β < 2. While the Lévy statistics for some animals require further study [14], Brockmann et al. [7] generalized this finding to humans, documenting that the distribution of distances between consecutive sight

Oxidative stress and low-grade inflammation are the hallmarks of the aging process and are even more enhanced in many age-related degenerative diseases. Mitochondrial dysfunction and oxidative stress can provoke and potentiate inflammatory responses, but the mechanism has remained elusive. Recent studies indicate that oxidative stress can induce the assembly of multiprotein inflammatory complexes called the inflammasomes. Nod-like receptor protein 3 (NLRP3) is the major immune sensor for cellular stress signals, e.g., reactive oxygen species, ceramides, and cathepsin B. NLRP3 activation triggers the caspase-1-mediated maturation of the precursors of IL-1b and IL-18 cytokines. During aging, the autophagic clearance of mitochondria declines and dysfunctional mitochondria provoke chronic oxidative stress, which disturbs the cellular redox balance. Moreover, increased NF-jB signaling observed during aging could potentiate the expression of NLRP3 and cytokine proforms enhancing the priming of NLRP3 inflammasomes. Recent studies have demonstrated that NLRP3 activation is associated with several age-related diseases, e.g., the metabolic syndrome. We will review here the emerging field of inflammasomes in the appearance of the proinflammatory phenotype during the aging process and in age-related diseases.

The realization of conservation goals requires strategies for managing whole landscapes including areas allocated to both production and protection. Reserves alone are not adequate for nature conservation but they are the cornerstone on which regional strategies are built. Reserves have two main roles. They should sample or represent the biodiversity of each region and they should separate this biodiversity from processes that threaten its persistence. Existing reserve systems throughout the world contain a biased sample of biodiversity, usually that of remote places and other areas that are unsuitable for commercial activities. A more systematic approach to locating and designing reserves has been evolving and this approach will need to be implemented if a large proportion of today's biodiversity is to exist in a future of increasing numbers of people and their demands on natural resources.

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the 14 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.

Development of the acute and chronic inflammatory responses known as gout and pseudogout are associated with the deposition of monosodium urate (MSU) or calcium pyrophosphate dihydrate (CPPD) crystals, respectively, in joints and periarticular tissues. Although MSU crystals ...

| In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.

Human alteration of the global environment has triggered the sixth major extinction event in the history of life and caused widespread changes in the global distribution of organisms. These changes in biodiversity alter ecosystem processes and change the resilience of ecosystems to environmental change. This has profound consequences for services that humans derive from ecosystems. The large ecological and societal consequences of changing biodiversity should be minimized to preserve options for future solutions to global environmental problems.

There is now ample evidence of the ecological impacts of recent climate change, from polar terrestrial to tropical marine environments. The responses of both¯ora and fauna span an array of ecosystems and organizational hierarchies, from the species to the community levels. Despite continued uncertainty as to community and ecosystem trajectories under global change, our review exposes a coherent pattern of ecological change across systems. Although we are only at an early stage in the projected trends of global warming, ecological responses to recent climate change are already clearly visible.

A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.

Antimetabolite drugs work by inhibiting essential biosynthetic processes, or by being incorporated into macromolecules, such as DNA and RNA, and inhibiting their normal function. The fluoropyrimidine 5-fluorouracil (5-FU) does both. FLUOROPYRIMIDINES were developed in the 1950s following the observation that rat hepatomas used the pyrimidine uracil-one of the four bases found in RNA-more rapidly than normal tissues, indicating that uracil metabolism was a potential target for antimetabolite chemotherapy 1. The mechanism of cytotoxicity of 5-FU has been ascribed to the misincorporation of fluoronucleotides into RNA and DNA and to the inhibition of the nucleotide synthetic enzyme thymidylate synthase (TS). 5-FU is widely used in the treatment of a range of cancers, including colorectal and breast cancers, and cancers of the aerodigestive tract. Although 5-FU in combination with other chemotherapeutic agents improves response rates and survival in breast and head and neck cancers, it is in colorectal cancer that 5-FU has had the greatest impact. 5-FU-based chemotherapy improves overall and disease-free survival of patients with resected stage III colorectal cancer 2. Nonetheless, response rates for 5-FU-based chemotherapy as a first-line treatment for advanced colorectal cancer are only 10-15% (REF. 3). The combination of 5-FU with newer chemotherapies such as IRINOTECAN and OXALIPLATIN has improved the response rates for advanced colorectal cancer to 40-50% (REFS 4,5). However, despite these improvements, new therapeutic strategies are urgently needed. Understanding the mechanisms by which 5-FU causes cell death and by which tumours become resistant to 5-FU is an essential step towards predicting or overcoming that resistance. So, what do we know about the mechanism of action of 5-FU and what strategies have been used to enhance its activity? DNA MICROARRAY technology has the potential to identify novel genes that have key roles in mediating resistance to 5-FU-based chemotherapy. Such genes might be therapeutically valuable as PREDICTIVE BIOMARKERS of 5-FU chemosensitivity and/or provide new molecular targets that overcome drug resistance. How have pre-clinical studies impacted on the clinical use of 5-FU and how might DNA microarray profiling affect its future clinical application? Mechanism of action of 5-FU 5-FU is an analogue of uracil with a fluorine atom at the C-5 position in place of hydrogen (FIG. 1). It rapidly enters the cell using the same facilitated transport mechanism as uracil 6. 5-FU is converted intracellularly to several active metabolites: fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine triphosphate (FdUTP) and fluorouridine triphosphate (FUTP) (FIG. 1)-these active metabolites disrupt RNA synthesis and the action of TS. The rate-limiting enzyme in 5-FU catabolism is dihydropyrimidine dehydrogenase (DPD), which converts 5-FU to dihydrofluorouracil (DHFU) 7. More than 80% of administered 5-FU is normally catabolized primarily in the liver, where DPD is abundantly expressed 7 .

Helicobacter pylori, strain 26695, has a circular genome of 1,667,867 base pairs and 1,590 predicted coding sequences. Sequence analysis indicates that H. pylori has well-developed systems for motility, for scavenging iron, and for DNA restriction and modification. Many putative adhesins, lipoproteins and other outer membrane proteins were identified, underscoring the potential complexity of host-pathogen interaction. Based on the large number of sequence-related genes encoding outer membrane proteins and the presence of homopolymeric tracts and dinucleotide repeats in coding sequences, H. pylori, like several other mucosal pathogens, probably uses recombination and slipped-strand mispairing within repeats as mechanisms for antigenic variation and adaptive evolution. Consistent with its restricted niche, H. pylori has a few regulatory networks, and a limited metabolic repertoire and biosynthetic capacity. Its survival in acid conditions depends, in part, on its ability to establish a positive inside-membrane potential in low pH. grant from the National Center for Research Resources. We thank N. S. Akopyants for preparing high quality chromosomal DNA from H. pylori strain 26695; M. Heaney, J. Scott, A. Saeed and R. Shirley for software and database support; and V. Sapiro, B. Vincent, J. Meehan and D. Mass for computer system support.

The Infrared Array Camera (IRAC) is one of three focal plane instruments in the Spitzer Space Telescope. IRAC is a four-channel camera that obtains simultaneous broad-band images at 3.6, 4.5, 5.8, and 8.0 microns. Two nearly adjacent 5.2x5.2 arcmin fields of view in the focal plane are viewed by the four channels in pairs (3.6 and 5.8 microns; 4.5 and 8 microns). All four detector arrays in the camera are 256x256 pixels in size, with the two shorter wavelength channels using InSb and the two longer wavelength channels using Si:As IBC detectors. IRAC is a powerful survey instrument because of its high sensitivity, large field of view, and four-color imaging. This paper summarizes the in-flight scientific, technical, and operational performance of IRAC.

The tumour-necrosis-factor-family molecule osteoprotegerin ligand (OPGL; also known as TRANCE, RANKL and ODF) has been identi®ed as a potential osteoclast differentiation factor and regulator of interactions between T cells and dendritic cells in vitro. Mice with a disrupted opgl gene show severe osteopetrosis and a defect in tooth eruption, and completely lack osteoclasts as a result of an inability of osteoblasts to support osteoclastogenesis. Although dendritic cells appear normal, opgl-de®cient mice exhibit defects in early differentiation of T and B lymphocytes. Surprisingly, opgl-de®cient mice lack all lymph nodes but have normal splenic structure and Peyer's patches. Thus OPGL is a new regulator of lymph-node organogenesis and lymphocyte development and is an essential osteoclast differentiation factor in vivo.

Viable tumour-derived epithelial cells (circulating tumour cells or CTCs) have been identified in peripheral blood from cancer patients and are probably the origin of intractable metastatic disease 1-4 . Although extremely rare, CTCs represent a potential alternative to invasive biopsies as a source of tumour tissue for the detection, characterization and monitoring of non-haematologic cancers 5-8 . The ability to identify, isolate, propagate and molecularly characterize CTC subpopulations could further the discovery of cancer stem cell biomarkers and expand the understanding of the biology of metastasis. Current strategies for isolating CTCs are limited to complex analytic approaches that generate very low yield and purity 9 . Here we describe the development of a unique microfluidic platform (the 'CTC-chip') capable of efficient and selective separation of viable CTCs from peripheral whole blood samples, mediated by the interaction of target CTCs with antibody (EpCAM)-coated microposts under precisely controlled laminar flow conditions, and without requisite pre-labelling or processing of samples. The CTC-chip successfully identified CTCs in the peripheral blood of patients with metastatic lung, prostate, pancreatic, breast and colon cancer in 115 of 116 (99%) samples, with a range of 5-1,281 CTCs per ml and approximately 50% purity. In addition, CTCs were isolated in 7/7 patients with earlystage prostate cancer. Given the high sensitivity and specificity of the CTC-chip, we tested its potential utility in monitoring response to anti-cancer therapy. In a small cohort of patients with metastatic cancer undergoing systemic treatment, temporal changes in CTC numbers correlated reasonably well with the clinical course of disease as measured by standard radiographic methods. Thus, the CTC-chip provides a new and effective tool for accurate identification and measurement of CTCs in patients with cancer. It has broad implications in advancing both cancer biology

Trust pervades human societies 1,2 . Trust is indispensable in friendship, love, families and organizations, and plays a key role in economic exchange and politics 3 . In the absence of trust among trading partners, market transactions break down. In the absence of trust in a country's institutions and leaders, political legitimacy breaks down. Much recent evidence indicates that trust contributes to economic, political and social success 4,5 . Little is known, however, about the biological basis of trust among humans. Here we show that intranasal administration of oxytocin, a neuropeptide that plays a key role in social attachment and affiliation in non-human mammals 6-8 , causes a substantial increase in trust among humans, thereby greatly increasing the benefits from social interactions. We also show that the effect of oxytocin on trust is not due to a general increase in the readiness to bear risks. On the contrary, oxytocin specifically affects an individual's willingness to accept social risks arising through interpersonal interactions. These results concur with animal research suggesting an essential role for oxytocin as a biological basis of prosocial approach behaviour.

The innate immune response is the first line of defence against infectious disease. The principal challenge for the host is to detect the pathogen and mount a rapid defensive response. A group of proteins that comprise the Toll or Toll-like family of receptors perform this role in vertebrate and invertebrate organisms. This reflects a remarkable conservation of function and it is therefore not surprising that studies of the mechanism by which they act has revealed new and important insights into host defence.

A central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis (‘cancer genes’). After two decades of searching, how many have been identified and how do they compare to the complete gene set that has been revealed by the human genome sequence? We have conducted a ‘census’ of cancer genes that indicates that mutations in more than 1% of genes contribute to human cancer. The census illustrates striking features in the types of sequence alteration, cancer classes in which oncogenic mutations have been identified and protein domains that are encoded by cancer genes.

Neuromotor prostheses (NMPs) aim to replace or restore lost motor functions in paralysed humans by routeing movement-related signals from the brain, around damaged parts of the nervous system, to external effectors. To translate preclinical results from intact animals to a clinically useful NMP, movement signals must persist in cortex after spinal cord injury and be engaged by movement intent when sensory inputs and limb movement are long absent. Furthermore, NMPs would require that intention-driven neuronal activity be converted into a control signal that enables useful tasks. Here we show initial results for a tetraplegic human (MN) using a pilot NMP. Neuronal ensemble activity recorded through a 96-microelectrode array implanted in primary motor cortex demonstrated that intended hand motion modulates cortical spiking patterns three years after spinal cord injury. Decoders were created, providing a 'neural cursor' with which MN opened simulated e-mail and operated devices such as a television, even while conversing. Furthermore, MN used neural control to open and close a prosthetic hand, and perform rudimentary actions with a multijointed robotic arm. These early results suggest that NMPs based upon intracortical neuronal ensemble spiking activity could provide a valuable new neurotechnology to restore independence for humans with paralysis.