The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress. Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings, suggesting that the ARF-p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF-p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF-p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress.

In the ovules of most sexual flowering plants female gametogenesis is initiated from a single surviving gametic cell, the functional megaspore, formed after meiosis of the somatically derived megaspore mother cell (MMC). Because some mutants and certain sexual species exhibit more than one MMC, and many others are able to form gametes without meiosis (by apomixis), it has been suggested that somatic cells in the ovule are competent to respond to a local signal likely to have an important function in determination. Here we show that the Arabidopsis protein ARGONAUTE 9 (AGO9) controls female gamete formation by restricting the specification of gametophyte precursors in a dosage-dependent, non-cell-autonomous manner. Mutations in AGO9 lead to the differentiation of multiple gametic cells that are able to initiate gametogenesis. The AGO9 protein is not expressed in the gamete lineage; instead, it is expressed in cytoplasmic foci of somatic companion cells. Mutations in SUPPRESSOR OF GENE SILENCING 3 and RNA-DEPENDENT RNA POLYMERASE 6 exhibit an identical defect to ago9 mutants, indicating that the movement of small RNA (sRNAs) silencing out of somatic companion cells is necessary for controlling the specification of gametic cells. AGO9 preferentially interacts with 24-nucleotide sRNAs derived from transposable elements (TEs), and its activity is necessary to silence TEs in female gametes and their accessory cells. Our results show that AGO9-dependent sRNA silencing is crucial to specify cell fate in the Arabidopsis ovule, and that epigenetic reprogramming in companion cells is necessary for sRNA-dependent silencing in plant gametes.

Epidermal growth factor receptor (EGFR) is a type I receptor tyrosine kinase, the deregulation of which has been implicated in a variety of human carcinomas. EGFR signalling is preceded by receptor dimerization, typically thought to result from a ligand-induced conformational change in the ectodomain that exposes a loop (dimerization arm) required for receptor association. Ligand binding may also trigger allosteric changes in the cytoplasmic domain of the receptor that is crucial for signalling. Despite these insights, ensemble-averaging approaches have not determined the precise mechanism of receptor activation in situ. Using quantum-dot-based optical tracking of single molecules combined with a novel time-dependent diffusivity analysis, here we present the dimerization dynamics of individual EGFRs on living cells. Before ligand addition, EGFRs spontaneously formed finite-lifetime dimers kinetically stabilized by their dimerization arms. The dimers were primed both for ligand binding and for signalling, such that after EGF addition they rapidly showed a very slow diffusivity state that correlated with activation. Although the kinetic stability of unliganded dimers was in principle sufficient for EGF-independent activation, ligand binding was still required for signalling. Interestingly, dimers were enriched in the cell periphery in an actin- and receptor-expression-dependent fashion, resulting in a peripheral enhancement of EGF-induced signalling that may enable polarized responses to growth factors.

Sirtuins are NAD(+)-dependent protein deacetylases. They mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized in the mitochondrial matrix, where it regulates the acetylation levels of metabolic enzymes, including acetyl coenzyme A synthetase 2 (refs 1, 2). Mice lacking both Sirt3 alleles appear phenotypically normal under basal conditions, but show marked hyperacetylation of several mitochondrial proteins. Here we report that SIRT3 expression is upregulated during fasting in liver and brown adipose tissues. During fasting, livers from mice lacking SIRT3 had higher levels of fatty-acid oxidation intermediate products and triglycerides, associated with decreased levels of fatty-acid oxidation, compared to livers from wild-type mice. Mass spectrometry of mitochondrial proteins shows that long-chain acyl coenzyme A dehydrogenase (LCAD) is hyperacetylated at lysine 42 in the absence of SIRT3. LCAD is deacetylated in wild-type mice under fasted conditions and by SIRT3 in vitro and in vivo; and hyperacetylation of LCAD reduces its enzymatic activity. Mice lacking SIRT3 exhibit hallmarks of fatty-acid oxidation disorders during fasting, including reduced ATP levels and intolerance to cold exposure. These findings identify acetylation as a novel regulatory mechanism for mitochondrial fatty-acid oxidation and demonstrate that SIRT3 modulates mitochondrial intermediary metabolism and fatty-acid use during fasting.

Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs) that activate innate immunity. Mitochondria are evolutionary endosymbionts that were derived from bacteria and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll-like receptor (TLR) 9, respectively. MTDs promote PMN Ca(2+) flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial 'enemies within' by cellular injury is a key link between trauma, inflammation and SIRS.

Hox genes are central to the specification of structures along the anterior-posterior body axis, and modifications in their expression have paralleled the emergence of diversity in vertebrate body plans. Here we describe the genomic organization of Hox clusters in different reptiles and show that squamates have accumulated unusually large numbers of transposable elements at these loci, reflecting extensive genomic rearrangements of coding and non-coding regulatory regions. Comparative expression analyses between two species showing different axial skeletons, the corn snake and the whiptail lizard, revealed major alterations in Hox13 and Hox10 expression features during snake somitogenesis, in line with the expansion of both caudal and thoracic regions. Variations in both protein sequences and regulatory modalities of posterior Hox genes suggest how this genetic system has dealt with its intrinsic collinear constraint to accompany the substantial morphological radiation observed in this group.

The early evolutionary history of Ornithodira (avian-line archosaurs) has hitherto been documented by incomplete (Lagerpeton) or unusually specialized forms (pterosaurs and Silesaurus). Recently, a variety of Silesaurus-like taxa have been reported from the Triassic period of both Gondwana and Laurasia, but their relationships to each other and to dinosaurs remain a subject of debate. Here we report on a new avian-line archosaur from the early Middle Triassic (Anisian) of Tanzania. Phylogenetic analysis places Asilisaurus kongwe gen. et sp. nov. as an avian-line archosaur and a member of the Silesauridae, which is here considered the sister taxon to Dinosauria. Silesaurids were diverse and had a wide distribution by the Late Triassic, with a novel ornithodiran bauplan including leaf-shaped teeth, a beak-like lower jaw, long, gracile limbs, and a quadrupedal stance. Our analysis suggests that the dentition and diet of silesaurids, ornithischians and sauropodomorphs evolved independently from a plesiomorphic carnivorous form. As the oldest avian-line archosaur, Asilisaurus demonstrates the antiquity of both Ornithodira and the dinosaurian lineage. The initial diversification of Archosauria, previously documented by crocodilian-line archosaurs in the Anisian, can now be shown to include a contemporaneous avian-line radiation. The unparalleled taxonomic diversity of the Manda archosaur assemblage indicates that archosaur diversification was well underway by the Middle Triassic or earlier.

Planar crack propagation under pure tension loading (mode I) is generally stable. However, it becomes universally unstable with the superposition of a shear stress parallel to the crack front (mode III). Under this mixed-mode (I + III) loading configuration, an initially flat parent crack segments into an array of daughter cracks that rotate towards a direction of maximum tensile stress. This segmentation produces stepped fracture surfaces with characteristic 'lance-shaped' markings observed in a wide range of engineering and geological materials. The origin of this instability remains poorly understood and a theory with which to predict the surface roughness scale is lacking. Here we perform large-scale simulations of mixed-mode I + III brittle fracture using a continuum phase-field method that describes the complete three-dimensional crack-front evolution. The simulations reveal that planar crack propagation is linearly unstable against helical deformations of the crack front, which evolve nonlinearly into a segmented array of finger-shaped daughter cracks. Furthermore, during their evolution, facets gradually coarsen owing to the growth competition of daughter cracks in striking analogy with the coarsening of finger patterns observed in nonequilibrium growth phenomena. We show that the dynamically preferred unstable wavelength is governed by the balance of the destabilizing effect of far-field stresses and the stabilizing effect of cohesive forces on the process zone scale, and we derive a theoretical estimate for this scale using a new propagation law for curved cracks in three dimensions. The rotation angles of coarsened facets are also compared to theoretical predictions and available experimental data.

Integration of optical communication circuits directly into high-performance microprocessor chips can enable extremely powerful computer systems. A germanium photodetector that can be monolithically integrated with silicon transistor technology is viewed as a key element in connecting chip components with infrared optical signals. Such a device should have the capability to detect very-low-power optical signals at very high speed. Although germanium avalanche photodetectors (APD) using charge amplification close to avalanche breakdown can achieve high gain and thus detect low-power optical signals, they are universally considered to suffer from an intolerably high amplification noise characteristic of germanium. High gain with low excess noise has been demonstrated using a germanium layer only for detection of light signals, with amplification taking place in a separate silicon layer. However, the relatively thick semiconductor layers that are required in such structures limit APD speeds to about 10 GHz, and require excessively high bias voltages of around 25 V (ref. 12). Here we show how nanophotonic and nanoelectronic engineering aimed at shaping optical and electrical fields on the nanometre scale within a germanium amplification layer can overcome the otherwise intrinsically poor noise characteristics, achieving a dramatic reduction of amplification noise by over 70 per cent. By generating strongly non-uniform electric fields, the region of impact ionization in germanium is reduced to just 30 nm, allowing the device to benefit from the noise reduction effects that arise at these small distances. Furthermore, the smallness of the APDs means that a bias voltage of only 1.5 V is required to achieve an avalanche gain of over 10 dB with operational speeds exceeding 30 GHz. Monolithic integration of such a device into computer chips might enable applications beyond computer optical interconnects-in telecommunications, secure quantum key distribution, and subthreshold ultralow-power transistors.

Efforts to identify and develop new superconducting materials continue apace, motivated by both fundamental science and the prospects for application. For example, several new superconducting material systems have been developed in the recent past, including calcium-intercalated graphite compounds, boron-doped diamond and-most prominently-iron arsenides such as LaO(1-x)F(x)FeAs (ref. 3). In the case of organic superconductors, however, no new material system with a high superconducting transition temperature (T(c)) has been discovered in the past decade. Here we report that intercalating an alkali metal into picene, a wide-bandgap semiconducting solid hydrocarbon, produces metallic behaviour and superconductivity. Solid potassium-intercalated picene (K(x)picene) shows T(c) values of 7 K and 18 K, depending on the metal content. The drop of magnetization in K(x)picene solids at the transition temperature is sharp (<2 K), similar to the behaviour of Ca-intercalated graphite. The T(c) of 18 K is comparable to that of K-intercalated C(60) (ref. 4). This discovery of superconductivity in K(x)picene shows that organic hydrocarbons are promising candidates for improved T(c) values.

Current cosmological models indicate that the Milky Way's stellar halo was assembled from many smaller systems. On the basis of the apparent absence of the most metal-poor stars in present-day dwarf galaxies, recent studies claimed that the true Galactic building blocks must have been vastly different from the surviving dwarfs. The discovery of an extremely iron-poor star (S1020549) in the Sculptor dwarf galaxy based on a medium-resolution spectrum cast some doubt on this conclusion. Verification of the iron-deficiency, however, and measurements of additional elements, such as the alpha-element Mg, are necessary to demonstrate that the same type of stars produced the metals found in dwarf galaxies and the Galactic halo. Only then can dwarf galaxy stars be conclusively linked to early stellar halo assembly. Here we report high-resolution spectroscopic abundances for 11 elements in S1020549, confirming its iron abundance of less than 1/4,000th that of the Sun, and showing that the overall abundance pattern follows that seen in low-metallicity halo stars, including the alpha-elements. Such chemical similarity indicates that the systems destroyed to form the halo billions of years ago were not fundamentally different from the progenitors of present-day dwarfs, and suggests that the early chemical enrichment of all galaxies may be nearly identical.

To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.

Over the past several decades, quantum information science has emerged to seek answers to the question: can we gain some advantage by storing, transmitting and processing information encoded in systems that exhibit unique quantum properties? Today it is understood that the answer is yes, and many research groups around the world are working towards the highly ambitious technological goal of building a quantum computer, which would dramatically improve computational power for particular tasks. A number of physical systems, spanning much of modern physics, are being developed for quantum computation. However, it remains unclear which technology, if any, will ultimately prove successful. Here we describe the latest developments for each of the leading approaches and explain the major challenges for the future.