Muscle specific kinase protects dystrophic mdx mouse muscles from eccentric contraction-induced loss of force-producing capacity.

KEY POINTS: Adeno-associated viral vector was used to elevate the expression of muscle specific kinase (MuSK) and rapsyn (a cytoplasmic MuSK effector protein) in the tibialis anterior muscle of wild-type and dystrophic (mdx) mice. In mdx mice, enhanced expression of either MuSK or rapsyn ameliorated the acute loss of muscle force associated with strain injury. Increases in sarcolemmal immunolabelling for utrophin and ß-dystroglycan suggest a mechanism for the protective effect of MuSK in mdx muscles. MuSK also caused subtle changes to the structure and function of the neuromuscular junction, suggesting novel roles for MuSK in muscle physiology and pathophysiology. ABSTRACT: Muscle specific kinase (MuSK) has a well-defined role in stabilizing the developing mammalian neuromuscular junction, but MuSK might also be protective in some neuromuscular diseases. In the dystrophin-deficient mdx mouse model of Duchenne muscular dystrophy, limb muscles are especially fragile. We injected the tibialis anterior muscle of 8-week-old mdx and wild-type (C57BL10) mice with adeno-associated viral vectors encoding either MuSK or rapsyn (a cytoplasmic MuSK effector protein) fused to green fluorescent protein (MuSK-GFP and rapsyn-GFP, respectively). Contralateral muscles injected with empty vector served as controls. One month later mice were anaesthetized with isoflurane and isometric force-producing capacity was recorded from the distal tendon. MuSK-GFP caused an unexpected decay in nerve-evoked tetanic force, both in wild-type and mdx muscles, without affecting contraction elicited by direct electrical stimulation of the muscle. Muscle fragility was probed by challenging muscles with a strain injury protocol consisting of a series of four strain-producing eccentric contractions in vivo. When applied to muscles of mdx mice, eccentric contraction produced an acute 27% reduction in directly evoked muscle force output, affirming the susceptibility of mdx muscles to strain injury. mdx muscles overexpressing MuSK-GFP or rapsyn-GFP exhibited significantly milder force deficits after the eccentric contraction challenge (15% and 14%, respectively). The protective effect of MuSK-GFP in muscles of mdx mice was associated with increased immunolabelling for utrophin and ß-dystroglycan in the sarcolemma. Elevating the expression of MuSK or rapsyn revealed several distinct synaptic and extrasynaptic effects, suggesting novel roles for MuSK signalling in muscle physiology and pathophysiology.

Guidelines for pre-clinical animal and cellular models of MuSK-myasthenia gravis.

Muscle-specific tyrosine kinase (MuSK) autoantibodies are the hallmark of a form of myasthenia gravis (MG) that can challenge the neurologist and the experimentalist. The clinical disease can be difficult to treat effectively. MuSK autoantibodies affect the neuromuscular junction in several ways. When added to muscle cells in culture, MuSK antibodies disperse acetylcholine receptor clusters. Experimental animals actively immunized with MuSK develop MuSK autoantibodies and muscle weakness. Weakness is associated with reduced postsynaptic acetylcholine receptor numbers, reduced amplitudes of miniature endplate potentials and endplate potentials, and failure of neuromuscular transmission. Similar impairments have been found in mice injected with IgG from MG patients positive for MuSK autoantibody (MuSK-MG). The active and passive models have begun to reveal the mechanisms by which MuSK antibodies disrupt synaptic function at the neuromuscular junction, and should be valuable in developing therapies for MuSK-MG. However, translation into new and improved treatments for patients requires procedures that are not too cumbersome but suitable for examining different aspects of MuSK function and the effects of potential therapies. Study design, conduct and analysis should be carefully considered and transparently reported. Here we review what has been learnt from animal and culture models of MuSK-MG, and offer guidelines for experimental design and conduct of studies, including sample size determination, randomization, outcome parameters and precautions for objective data analysis. These principles may also be relevant to the increasing number of other antibody-mediated diseases that are now recognized.

Driving phase slips in a superfluid atom circuit with a rotating weak link.

We have observed well-defined phase slips between quantized persistent current states around a toroidal atomic (23Na) Bose-Einstein condensate. These phase slips are induced by a weak link (a localized region of reduced superfluid density) rotated slowly around the ring. This is analogous to the behavior of a superconducting loop with a weak link in the presence of an external magnetic field. When the weak link is rotated more rapidly, well-defined phase slips no longer occur, and vortices enter into the bulk of the condensate. A noteworthy feature of this system is the ability to dynamically vary the current-phase relation of the weak link, a feature which is difficult to implement in superconducting or superfluid helium circuits.

Synthetic partial waves in ultracold atomic collisions.

Interactions between particles can be strongly altered by their environment. We demonstrate a technique for modifying interactions between ultracold atoms by dressing the bare atomic states with light, creating an effective interaction of vastly increased range that scatters states of finite relative angular momentum at collision energies where only s-wave scattering would normally be expected. We collided two optically dressed neutral atomic Bose-Einstein condensates with equal, and opposite, momenta and observed that the usual s-wave distribution of scattered atoms was altered by the appearance of d- and g-wave contributions. This technique is expected to enable quantum simulation of exotic systems, including those predicted to support Majorana fermions.

Superflow in a toroidal Bose-Einstein condensate: an atom circuit with a tunable weak link.

We have created a long-lived (≈40 s) persistent current in a toroidal Bose-Einstein condensate held in an all-optical trap. A repulsive optical barrier across one side of the torus creates a tunable weak link in the condensate circuit, which can affect the current around the loop. Superflow stops abruptly at a barrier strength such that the local flow velocity at the barrier exceeds a critical velocity. The measured critical velocity is consistent with dissipation due to the creation of vortex-antivortex pairs. This system is the first realization of an elementary closed-loop atom circuit.

Phases of a two-dimensional bose gas in an optical lattice.

Ultracold atoms in optical lattices realize simple condensed matter models. We create an ensemble of ≈60 harmonically trapped 2D Bose-Hubbard systems from a 87Rb Bose-Einstein condensate in an optical lattice and use a magnetic resonance imaging approach to select a few 2D systems for study, thereby eliminating ensemble averaging. Our identification of the transition from superfluid to Mott insulator, as a function of both atom density and lattice depth, is in excellent agreement with a universal state diagram [M. Rigol, Phys. Rev. A 79 053605 (2009)] suitable for our trapped system. In agreement with theory, our data suggest a failure of the local density approximation in the transition region.

Patient autoantibodies deplete postsynaptic muscle-specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice.

The postsynaptic muscle-specific kinase (MuSK) coordinates formation of the neuromuscular junction (NMJ) during embryonic development. Here we have studied the effects of MuSK autoantibodies upon the NMJ in adult mice. Daily injections of IgG from four MuSK autoantibody-positive myasthenia gravis patients (MuSK IgG; 45 mg day(1)i.p. for 14 days) caused reductions in postsynaptic ACh receptor (AChR) packing as assessed by fluorescence resonance energy transfer (FRET). IgG from the patients with the highest titres of MuSK autoantibodies caused large (51-73%) reductions in postsynaptic MuSK staining (cf. control mice; P < 0.01) and muscle weakness. Among mice injected for 14 days with control and MuSK patient IgGs, the residual level of MuSK correlated with the degree of impairment of postsynaptic AChR packing. However, the loss of postsynaptic MuSK preceded this impairment of postsynaptic AChR. When added to cultured C2 muscle cells the MuSK autoantibodies caused tyrosine phosphorylation of MuSK and the AChR beta-subunit, and internalization of MuSK from the plasma membrane. The results suggest a pathogenic mechanism in which MuSK autoantibodies rapidly deplete MuSK from the postsynaptic membrane leading to progressive dispersal of postsynaptic AChRs. Moreover, maintenance of postsynaptic AChR packing at the adult NMJ would appear to depend upon physical engagement of MuSK with the AChR scaffold, notwithstanding activation of the MuSK-rapsyn system of AChR clustering.

Observation of a 2D Bose gas: from thermal to quasicondensate to superfluid.

We present experimental results on a Bose gas in a quasi-2D geometry near the Berezinskii, Kosterlitz, and Thouless (BKT) transition temperature. By measuring the density profile after time of flight and the coherence length, we identify different states of the gas. We observe that the gas develops a bimodal distribution without long range order. In this regime, the gas presents a longer coherence length than the thermal cloud; it is quasicondensed but is not superfluid. Experimental evidence indicates that we also observe the superfluid transition (BKT transition). For a sufficiently long time of flight, we observe a trimodal distribution when the gas has developed a superfluid component.

Bose-Einstein condensate in a uniform light-induced vector potential.

We use a two-photon dressing field to create an effective vector gauge potential for Bose-Einstein-condensed 87Rb atoms in the F=1 hyperfine ground state. These Raman-dressed states are spin and momentum superpositions, and we adiabatically load the atoms into the lowest energy dressed state. The effective Hamiltonian of these neutral atoms is like that of charged particles in a uniform magnetic vector potential whose magnitude is set by the strength and detuning of the Raman coupling. The spin and momentum decomposition of the dressed states reveals the strength of the effective vector potential, and our measurements agree quantitatively with a simple single-particle model. While the uniform effective vector potential described here corresponds to zero magnetic field, our technique can be extended to nonuniform vector potentials, giving nonzero effective magnetic fields.

Quantum and classical dynamics of a Bose-Einstein condensate in a large-period optical lattice.

We experimentally investigate diffraction of a 87Rb Bose-Einstein condensate from a one-dimensional optical lattice. We use a range of lattice periods and timescales, including those beyond the Raman-Nath limit. We compare the results to numerical solutions of the Gross-Pitaevskii equation and classical calculations, with quantitative and qualitative agreement, respectively. The classical calculations predict that the envelope of the time-evolving diffraction pattern is shaped by caustics: singularities in the phase-space density of classical trajectories. This behavior becomes increasingly clear as the lattice period grows.

Condensate fraction in a 2D Bose gas measured across the Mott-insulator transition.

We realize a single-band 2D Bose-Hubbard system with Rb atoms in an optical lattice and measure the condensate fraction as a function of lattice depth, crossing from the superfluid to the Mott-insulating phase. We quantitatively identify the location of the superfluid to normal transition by observing when the condensed fraction vanishes. Our measurement agrees with recent quantum Monte Carlo calculations for a finite-sized 2D system to within experimental uncertainty.

Atoms in a radio-frequency-dressed optical lattice.

We load cold atoms into an optical lattice dramatically reshaped by radio-frequency coupling of state-dependent lattice potentials. This radio-frequency dressing changes the unit cell of the lattice at a subwavelength scale, such that its curvature and topology departs strongly from that of a simple sinusoidal lattice potential. Radio-frequency dressing has previously been performed at length scales from mm to tens of mum, but not at the single-optical-wavelength scale. At this length scale significant coupling between adiabatic potentials leads to nonadiabatic transitions, which we measure as a function of lattice depth and dressing amplitude. We also investigate the dressing by measuring changes in the momentum distribution of the dressed states.

Preparing and probing atomic number states with an atom interferometer.

We describe the controlled loading and measurement of number-squeezed states and Poisson states of atoms in individual sites of a double well optical lattice. These states are input to an atom interferometer that is realized by symmetrically splitting individual lattice sites into double wells, allowing atoms in individual sites to evolve independently. The two paths then interfere, creating a matter-wave double-slit diffraction pattern. The time evolution of the double-slit diffraction pattern is used to measure the number statistics of the input state. The flexibility of our double well lattice provides a means to detect the presence of empty lattice sites, an important and so far unmeasured factor in determining the purity of a Mott state.

Sublattice addressing and spin-dependent motion of atoms in a double-well lattice.

We load atoms into every site of an optical lattice and selectively spin flip atoms in a sublattice consisting of every other site. These selected atoms are separated from their unselected neighbors by less than an optical wavelength. We also show spin-dependent transport, where atomic wave packets are coherently separated into adjacent sites according to their internal state. These tools should be useful for quantum information processing and quantum simulation of lattice models with neutral atoms.

Mott-insulator transition in a two-dimensional atomic Bose gas.

Cold atoms in periodic potentials are versatile quantum systems for implementing simple models prevalent in condensed matter theory. Here we realize the 2D Bose-Hubbard model by loading a Bose-Einstein condensate into an optical lattice, and study the resulting Mott insulator. The measured momentum distributions agree quantitatively with theory (no adjustable parameters). In these systems, the Mott insulator forms in a spatially discrete shell structure which we probe by focusing on correlations in atom shot noise. These correlations show a marked dependence on the lattice depth, consistent with the changing size of the insulating shell expected from simple arguments.

Observation of persistent flow of a Bose-Einstein condensate in a toroidal trap.

We have observed the persistent flow of Bose-condensed atoms in a toroidal trap. The flow persists without decay for up to 10 s, limited only by experimental factors such as drift and trap lifetime. The quantized rotation was initiated by transferring one unit variant Planck's over 2pi of the orbital angular momentum from Laguerre-Gaussian photons to each atom. Stable flow was only possible when the trap was multiply connected, and was observed with a Bose-Einstein condensate fraction as small as 20%. We also created flow with two units of angular momentum and observed its splitting into two singly charged vortices when the trap geometry was changed from multiply to simply connected.

Quantized rotation of atoms from photons with orbital angular momentum.

We demonstrate the coherent transfer of the orbital angular momentum of a photon to an atom in quantized units of variant Planck's over 2pi, using a 2-photon stimulated Raman process with Laguerre-Gaussian beams to generate an atomic vortex state in a Bose-Einstein condensate of sodium atoms. We show that the process is coherent by creating superpositions of different vortex states, where the relative phase between the states is determined by the relative phases of the optical fields. Furthermore, we create vortices of charge 2 by transferring to each atom the orbital angular momentum of two photons.

High-order quantum resonances observed in a periodically kicked Bose-Einstein condensate.

We have observed high-order quantum resonances in a realization of the quantum delta-kicked rotor, using Bose-condensed Na atoms subjected to a pulsed standing wave of laser light. These resonances occur for pulse intervals that are rational fractions of the Talbot time, and are characterized by ballistic momentum transfer to the atoms. The condensate's narrow momentum distribution not only permits the observation of the quantum resonances at 3/4 and 1/3 of the Talbot time, but also allows us to study scaling laws for the resonance width in quasimomentum and pulse interval.

Strongly inhibited transport of a degenerate 1D Bose gas in a lattice.

We report the observation of strongly damped dipole oscillations of a quantum degenerate 1D atomic Bose gas in a combined harmonic and optical lattice potential. Damping is significant for very shallow axial lattices (0.25 photon recoil energies), and increases dramatically with increasing lattice depth, such that the gas becomes nearly immobile for times an order of magnitude longer than the single-particle tunneling time. Surprisingly, we see no broadening of the atomic quasimomentum distribution after damped motion. Recent theoretical work suggests that quantum fluctuations can strongly damp dipole oscillations of a 1D atomic Bose gas, providing a possible explanation for our observations.

Observation of reduced three-body recombination in a correlated 1D degenerate Bose gas.

We investigate the correlation properties of a one-dimensional interacting Bose gas by loading a magnetically trapped 87Rb Bose-Einstein condensate (BEC) into a deep two-dimensional optical lattice. We measure the three-body recombination rate for both the BEC in the magnetic trap and the BEC loaded into the optical lattice. The recombination rate coefficient is a factor of 7 smaller in the lattice, which we interpret as a reduction in the local three-body correlation function in the 1D case. This is a signature of correlation intermediate between that of the uncorrelated, phase coherent, 1D, mean-field regime and the strongly correlated Tonks-Girardeau regime.