Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia

Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer.     

14-3-3sigma controls mitotic translation to facilitate cytokinesis

14-3-3 proteins are crucial in a wide variety of cellular responses including cell cycle progression, DNA damage checkpoints and apoptosis. One particular 14-3-3 isoform, sigma, is a p53-responsive gene, the function of which is frequently lost in human tumours, including breast and prostate cancers as a result of either hypermethylation of the 14-3-3sigma promoter or induction of an oestrogen-responsive ubiquitin ligase that specifically targets 14-3-3sigma for proteasomal degradation. Loss of 14-3-3sigma protein occurs not only within the tumours themselves but also in the surrounding pre-dysplastic tissue (so-called field cancerization), indicating that 14-3-3sigma might have an important tumour suppressor function that becomes lost early in the process of tumour evolution. The molecular basis for the tumour suppressor function of 14-3-3sigma is unknown. Here we report a previously unknown function for 14-3-3sigma as a regulator of mitotic translation through its direct mitosis-specific binding to a variety of translation/initiation factors, including eukaryotic initiation factor 4B in a stoichiometric manner. Cells lacking 14-3-3sigma, in marked contrast to normal cells, cannot suppress cap-dependent translation and do not stimulate cap-independent translation during and immediately after mitosis. This defective switch in the mechanism of translation results in reduced mitotic-specific expression of the endogenous internal ribosomal entry site (IRES)-dependent form of the cyclin-dependent kinase Cdk11 (p58 PITSLRE), leading to impaired cytokinesis, loss of Polo-like kinase-1 at the midbody, and the accumulation of binucleate cells. The aberrant mitotic phenotype of 14-3-3sigma-depleted cells can be rescued by forced expression of p58 PITSLRE or by extinguishing cap-dependent translation and increasing cap-independent translation during mitosis by using rapamycin. Our findings show how aberrant mitotic translation in the absence of 14-3-3sigma impairs mitotic exit to generate binucleate cells and provides a potential explanation of how 14-3-3sigma-deficient cells may progress on the path to aneuploidy and tumorigenesis.     

Evolution and diversity of subduction zones controlled by slab width

Subducting slabs provide the main driving force for plate motion and flow in the Earth's mantle, and geodynamic, seismic and geochemical studies offer insight into slab dynamics and subduction-induced flow. Most previous geodynamic studies treat subduction zones as either infinite in trench-parallel extent (that is, two-dimensional) or finite in width but fixed in space. Subduction zones and their associated slabs are, however, limited in lateral extent (250-7,400 km) and their three-dimensional geometry evolves over time. Here we show that slab width controls two first-order features of plate tectonics-the curvature of subduction zones and their tendency to retreat backwards with time. Using three-dimensional numerical simulations of free subduction, we show that trench migration rate is inversely related to slab width and depends on proximity to a lateral slab edge. These results are consistent with retreat velocities observed globally, with maximum velocities (6-16 cm yr(-1)) only observed close to slab edges (<1,200 km), whereas far from edges (>2,000 km) retreat velocities are always slow (<2.0 cm yr(-1)). Models with narrow slabs (< or =1,500 km) retreat fast and develop a curved geometry, concave towards the mantle wedge side. Models with slabs intermediate in width ( approximately 2,000-3,000 km) are sublinear and retreat more slowly. Models with wide slabs (> or =4,000 km) are nearly stationary in the centre and develop a convex geometry, whereas trench retreat increases towards concave-shaped edges. Additionally, we identify periods (5-10 Myr) of slow trench advance at the centre of wide slabs. Such wide-slab behaviour may explain mountain building in the central Andes, as being a consequence of its tectonic setting, far from slab edges.     

Abrupt onset of a second energy gap at the superconducting transition of underdoped Bi2212

The superconducting gap--an energy scale tied to the superconducting phenomena--opens on the Fermi surface at the superconducting transition temperature (T(c)) in conventional BCS superconductors. In underdoped high-T(c) superconducting copper oxides, a pseudogap (whose relation to the superconducting gap remains a mystery) develops well above T(c) (refs 1, 2). Whether the pseudogap is a distinct phenomenon or the incoherent continuation of the superconducting gap above T(c) is one of the central questions in high-T(c) research. Although some experimental evidence suggests that the two gaps are distinct, this issue is still under intense debate. A crucial piece of evidence to firmly establish this two-gap picture is still missing: a direct and unambiguous observation of a single-particle gap tied to the superconducting transition as function of temperature. Here we report the discovery of such an energy gap in underdoped Bi2Sr2CaCu2O8+delta in the momentum space region overlooked in previous measurements. Near the diagonal of Cu-O bond direction (nodal direction), we found a gap that opens at T(c) and has a canonical (BCS-like) temperature dependence accompanied by the appearance of the so-called Bogoliubov quasi-particles, a classical signature of superconductivity. This is in sharp contrast to the pseudogap near the Cu-O bond direction (antinodal region) measured in earlier experiments.     

Controlled exchange interaction between pairs of neutral atoms in an optical lattice

Ultracold atoms trapped by light offer robust quantum coherence and controllability, providing an attractive system for quantum information processing and for the simulation of complex problems in condensed matter physics. Many quantum information processing schemes require the manipulation and deterministic entanglement of individual qubits; this would typically be accomplished using controlled, state-dependent, coherent interactions among qubits. Recent experiments have made progress towards this goal by demonstrating entanglement among an ensemble of atoms confined in an optical lattice. Until now, however, there has been no demonstration of a key operation: controlled entanglement between atoms in isolated pairs. Here we use an optical lattice of double-well potentials to isolate and manipulate arrays of paired (87)Rb atoms, inducing controlled entangling interactions within each pair. Our experiment realizes proposals to use controlled exchange coupling in a system of neutral atoms. Although 87Rb atoms have nearly state-independent interactions, when we force two atoms into the same physical location, the wavefunction exchange symmetry of these identical bosons leads to state-dependent dynamics. We observe repeated interchange of spin between atoms occupying different vibrational levels, with a coherence time of more than ten milliseconds. This observation demonstrates the essential component of a neutral atom quantum SWAP gate (which interchanges the state of two qubits). Its 'half-implementation', the root SWAP gate, is entangling, and together with single-qubit rotations it forms a set of universal gates for quantum computation.     

Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3

Oncogenic tyrosine kinases have proved to be promising targets for the development of highly effective anticancer drugs. However, tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (HER) family show only limited activity against HER2-driven breast cancers, despite effective inhibition of epidermal growth factor receptor (EGFR) and HER2 in vivo. The reasons for this are unclear. Signalling in trans is a key feature of this multimember family and the critically important phosphatidylinositol-3-OH kinase (PI(3)K)/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 (refs 9, 10). Here we show that HER3 and consequently PI(3)K/Akt signalling evade inhibition by current HER-family TKIs in vitro and in tumours in vivo. This is due to a compensatory shift in the HER3 phosphorylation-dephosphorylation equilibrium, driven by increased membrane HER3 expression driving the phosphorylation reaction and by reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt-mediated negative-feedback signalling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abrogation of HER3 resistance by small interfering RNA knockdown restores potent pro-apoptotic activity to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumours and the therapeutic promise of this oncoprotein target. However, because HER3 signalling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to silence oncogenic HER2 signalling effectively. The biologic marker with which to assess the efficacy of HER TKIs should be the transphosphorylation of HER3 rather than autophosphorylation.     

The sources of sodium escaping from Io revealed by spectral high definition imaging

On Jupiter's moon Io, volcanic plumes and evaporating lava flows provide hot gases to form an atmosphere that is subsequently ionized. Some of Io's plasma is captured by the planet's strong magnetic field to form a co-rotating torus at Io's distance; the remaining ions and electrons form Io's ionosphere. The torus and ionosphere are also depleted by three time-variable processes that produce a banana-shaped cloud orbiting with Io, a giant nebula extending out to about 500 Jupiter radii, and a jet close to Io. No spatial constraints exist for the sources of the first two; they have been inferred only from modelling the patterns seen in the trace gas sodium observed far from Io. Here we report observations that reveal a spatially confined stream that ejects sodium only from the wake of the Io-torus interaction, together with a visually distinct, spherically symmetrical outflow region arising from atmospheric sputtering. The spatial extent of the ionospheric wake that feeds the stream is more than twice that observed by the Galileo spacecraft and modelled successfully. This implies considerable variability, and therefore the need for additional modelling of volcanically-driven, episodic states of the great jovian nebula.