Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase

Cellular growth and proliferation are coordinated during organogenesis. Misregulation of these processes leads to pathological conditions such as cancer. Tuberous sclerosis (TSC) is a benign tumour syndrome caused by mutations in either TSC1 or TSC2 tumour suppressor genes. Studies in Drosophila and other organisms have identified TSC signalling as a conserved pathway for growth control. Activation of the TSC pathway is mediated by Rheb (Ras homologue enriched in brain), a Ras superfamily GTPase. Rheb is a direct target of TSC2 and is negatively regulated by its GTPase-activating protein activity. However, molecules required for positive regulation of Rheb have not been identified. Here we show that a conserved protein, translationally controlled tumour protein (TCTP), is an essential new component of the TSC-Rheb pathway. Reducing Drosophila TCTP (dTCTP) levels reduces cell size, cell number and organ size, which mimics Drosophila Rheb (dRheb) mutant phenotypes. dTCTP is genetically epistatic to Tsc1 and dRheb, but acts upstream of dS6k, a downstream target of dRheb. dTCTP directly associates with dRheb and displays guanine nucleotide exchange activity with it in vivo and in vitro. Human TCTP (hTCTP) shows similar biochemical properties compared to dTCTP and can rescue dTCTP mutant phenotypes, suggesting that the function of TCTP in the TSC pathway is evolutionarily conserved. Our studies identify TCTP as a direct regulator of Rheb and a potential therapeutic target for TSC disease.     

Early gas stripping as the origin of the darkest galaxies in the Universe

The known galaxies most dominated by dark matter (Draco, Ursa Minor and Andromeda IX) are satellites of the Milky Way and the Andromeda galaxies. They are members of a class of faint galaxies, devoid of gas, known as dwarf spheroidals, and have by far the highest ratio of dark to luminous matter. None of the models proposed to unravel their origin can simultaneously explain their exceptional dark matter content and their proximity to a much larger galaxy. Here we report simulations showing that the progenitors of these galaxies were probably gas-dominated dwarf galaxies that became satellites of a larger galaxy earlier than the other dwarf spheroidals. We find that a combination of tidal shocks and ram pressure swept away the entire gas content of such progenitors about ten billion years ago because heating by the cosmic ultraviolet background kept the gas loosely bound: a tiny stellar component embedded in a relatively massive dark halo survived until today. All luminous galaxies should be surrounded by a few extremely dark-matter-dominated dwarf spheroidal satellites, and these should have the shortest orbital periods among dwarf spheroidals because they were accreted early.     

Structural definition of a conserved neutralization epitope on HIV-1 gp120

The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 A resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.     

Lanthanide contraction and magnetism in the heavy rare earth elements

The heavy rare earth elements crystallize into hexagonally close packed (h.c.p.) structures and share a common outer electronic configuration, differing only in the number of 4f electrons they have. These chemically inert 4f electrons set up localized magnetic moments, which are coupled via an indirect exchange interaction involving the conduction electrons. This leads to the formation of a wide variety of magnetic structures, the periodicities of which are often incommensurate with the underlying crystal lattice. Such incommensurate ordering is associated with a 'webbed' topology of the momentum space surface separating the occupied and unoccupied electron states (the Fermi surface). The shape of this surface-and hence the magnetic structure-for the heavy rare earth elements is known to depend on the ratio of the interplanar spacing c and the interatomic, intraplanar spacing a of the h.c.p. lattice. A theoretical understanding of this problem is, however, far from complete. Here, using gadolinium as a prototype for all the heavy rare earth elements, we generate a unified magnetic phase diagram, which unequivocally links the magnetic structures of the heavy rare earths to their lattice parameters. In addition to verifying the importance of the c/a ratio, we find that the atomic unit cell volume plays a separate, distinct role in determining the magnetic properties: we show that the trend from ferromagnetism to incommensurate ordering as atomic number increases is connected to the concomitant decrease in unit cell volume. This volume decrease occurs because of the so-called lanthanide contraction, where the addition of electrons to the poorly shielding 4f orbitals leads to an increase in effective nuclear charge and, correspondingly, a decrease in ionic radii.     

Chemical rescue of cleft palate and midline defects in conditional GSK-3beta mice

Glycogen synthase kinase-3beta (GSK-3beta) has integral roles in a variety of biological processes, including development, diabetes, and the progression of Alzheimer's disease. As such, a thorough understanding of GSK-3beta function will have a broad impact on human biology and therapeutics. Because GSK-3beta interacts with many different pathways, its specific developmental roles remain unclear. We have discovered a genetic requirement for GSK-3beta in midline development. Homozygous null mice display cleft palate, incomplete fusion of the ribs at the midline and bifid sternum as well as delayed sternal ossification. Using a chemically regulated allele of GSK-3beta (ref. 6), we have defined requirements for GSK-3beta activity during discrete temporal windows in palatogenesis and skeletogenesis. The rapamycin-dependent allele of GSK-3beta produces GSK-3beta fused to a tag, FRB* (FKBP/rapamycin binding), resulting in a rapidly destabilized chimaeric protein. In the absence of drug, GSK-3beta(FRB)*(/FRB)* mutants appear phenotypically identical to GSK-3beta-/- mutants. In the presence of drug, GSK-3betaFRB* is rapidly stabilized, restoring protein levels and activity. Using this system, mutant phenotypes were rescued by restoring endogenous GSK-3beta activity during two distinct periods in gestation. This technology provides a powerful tool for defining windows of protein function during development.     

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.     

Fluctuating valence in a correlated solid and the anomalous properties of delta-plutonium

Although the nuclear properties of the late actinides (plutonium, americium and curium) are fully understood and widely applied to energy generation, their solid-state properties do not fit within standard models and are the subject of active research. Plutonium displays phases with enormous volume differences, and both its Pauli-like magnetic susceptibility and resistivity are an order of magnitude larger than those of simple metals. Curium is also highly resistive, but its susceptibility is Curie-like at high temperatures and orders antiferromagnetically at low temperatures. The anomalous properties of the late actinides stem from the competition between itinerancy and localization of their f-shell electrons, which makes these elements strongly correlated materials. A central problem in this field is to understand the mechanism by which these conflicting tendencies are resolved in such materials. Here we identify the electronic mechanisms responsible for the anomalous behaviour of late actinides, revisiting the concept of valence using a theoretical approach that treats magnetism, Kondo screening, atomic multiplet effects and crystal field splitting on the same footing. We find that the ground state in plutonium is a quantum superposition of two distinct atomic valences, whereas curium settles into a magnetically ordered single valence state at low temperatures. The f(7) configuration of curium is contrasted with the multiple valences of the plutonium ground state, which we characterize by a valence histogram. The balance between the Kondo screening and magnetism is controlled by the competition between spin-orbit coupling, the strength of atomic multiplets and the degree of itinerancy. Our approach highlights the electronic origin of the bonding anomalies in plutonium, and can be applied to predict generalized valences and the presence or absence of magnetism in other compounds starting from first principles.     

Demonstration of controlled-NOT quantum gates on a pair of superconducting quantum bits

Quantum computation requires quantum logic gates that use the interaction within pairs of quantum bits (qubits) to perform conditional operations. Superconducting qubits may offer an attractive route towards scalable quantum computing. In previous experiments on coupled superconducting qubits, conditional gate behaviour and entanglement were demonstrated. Here we demonstrate selective execution of the complete set of four different controlled-NOT (CNOT) quantum logic gates, by applying microwave pulses of appropriate frequency to a single pair of coupled flux qubits. All two-qubit computational basis states and their superpositions are used as input, while two independent single-shot SQUID detectors measure the output state, including qubit-qubit correlations. We determined the gate's truth table by directly measuring the state transfer amplitudes and by acquiring the relevant quantum phase shift using a Ramsey-like interference experiment. The four conditional gates result from the symmetry of the qubits in the pair: either qubit can assume the role of control or target, and the gate action can be conditioned on either the 0-state or the 1-state. These gates are now sufficiently characterized to be used in quantum algorithms, and together form an efficient set of versatile building blocks.