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.     

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.     

Observation of the two-channel Kondo effect

Some of the most intriguing problems in solid-state physics arise when the motion of one electron dramatically affects the motion of surrounding electrons. Traditionally, such highly correlated electron systems have been studied mainly in materials with complex transition metal chemistry. Over the past decade, researchers have learned to confine one or a few electrons within a nanometre-scale semiconductor 'artificial atom', and to understand and control this simple system in detail(3). Here we combine artificial atoms to create a highly correlated electron system within a nano-engineered semiconductor structure. We tune the system in situ through a quantum phase transition between two distinct states, each a version of the Kondo state, in which a bound electron interacts with surrounding mobile electrons. The boundary between these competing Kondo states is a quantum critical point-namely, the exotic and previously elusive two-channel Kondo state, in which electrons in two reservoirs are entangled through their interaction with a single localized spin.     

Semaphorin 7A initiates T-cell-mediated inflammatory responses through alpha1beta1 integrin

Semaphorins are axon guidance factors that assist growing axons in finding appropriate targets and forming synapses. Emerging evidence suggests that semaphorins are involved not only in embryonic development but also in immune responses. Semaphorin 7A (Sema7A; also known as CD108), which is a glycosylphosphatidylinositol-anchored semaphorin, promotes axon outgrowth through beta1-integrin receptors and contributes to the formation of the lateral olfactory tract. Although Sema7A has been shown to stimulate human monocytes, its function as a negative regulator of T-cell responses has also been reported. Thus, the precise function of Sema7A in the immune system remains unclear. Here we show that Sema7A, which is expressed on activated T cells, stimulates cytokine production in monocytes and macrophages through alpha1beta1 integrin (also known as very late antigen-1) as a component of the immunological synapse, and is critical for the effector phase of the inflammatory immune response. Sema7A-deficient (Sema7a-/-) mice are defective in cell-mediated immune responses such as contact hypersensitivity and experimental autoimmune encephalomyelitis. Although antigen-specific and cytokine-producing effector T cells can develop and migrate into antigen-challenged sites in Sema7a-/- mice, Sema7a-/- T cells fail to induce contact hypersensitivity even when directly injected into the antigen-challenged sites. Thus, the interaction between Sema7A and alpha1beta1 integrin is crucial at the site of inflammation. These findings not only identify a function of Sema7A as an effector molecule in T-cell-mediated inflammation, but also reveal a mechanism of integrin-mediated immune regulation.     

Exploitation of structural and regulatory diversity in glutamate racemases

Glutamate racemase is an enzyme essential to the bacterial cell wall biosynthesis pathway, and has therefore been considered as a target for antibacterial drug discovery. We characterized the glutamate racemases of several pathogenic bacteria using structural and biochemical approaches. Here we describe three distinct mechanisms of regulation for the family of glutamate racemases: allosteric activation by metabolic precursors, kinetic regulation through substrate inhibition, and D-glutamate recycling using a d-amino acid transaminase. In a search for selective inhibitors, we identified a series of uncompetitive inhibitors specifically targeting Helicobacter pylori glutamate racemase that bind to a cryptic allosteric site, and used these inhibitors to probe the mechanistic and dynamic features of the enzyme. These structural, kinetic and mutational studies provide insight into the physiological regulation of these essential enzymes and provide a basis for designing narrow-spectrum antimicrobial agents.     

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.     

A flagellin-induced complex of the receptor FLS2 and BAK1 initiates plant defence

Plants sense potential microbial invaders by using pattern-recognition receptors to recognize pathogen-associated molecular patterns (PAMPs). In Arabidopsis thaliana, the leucine-rich repeat receptor kinases flagellin-sensitive 2 (FLS2) (ref. 2) and elongation factor Tu receptor (EFR) (ref. 3) act as pattern-recognition receptors for the bacterial PAMPs flagellin and elongation factor Tu (EF-Tu) (ref. 5) and contribute to resistance against bacterial pathogens. Little is known about the molecular mechanisms that link receptor activation to intracellular signal transduction. Here we show that BAK1 (BRI1-associated receptor kinase 1), a leucine-rich repeat receptor-like kinase that has been reported to regulate the brassinosteroid receptor BRI1 (refs 6,7), is involved in signalling by FLS2 and EFR. Plants carrying bak1 mutations show normal flagellin binding but abnormal early and late flagellin-triggered responses, indicating that BAK1 acts as a positive regulator in signalling. The bak1-mutant plants also show a reduction in early, but not late, EF-Tu-triggered responses. The decrease in responses to PAMPs is not due to reduced sensitivity to brassinosteroids. We provide evidence that FLS2 and BAK1 form a complex in vivo, in a specific ligand-dependent manner, within the first minutes of stimulation with flagellin. Thus, BAK1 is not only associated with developmental regulation through the plant hormone receptor BRI1 (refs 6,7), but also has a functional role in PRR-dependent signalling, which initiates innate immunity.