Synaptic Activity Causes Minute-scale Changes in BAF Complex Composition and Function.

Genes encoding subunits of the SWI/SNF or BAF ATP-dependent chromatin remodeling complex are among the most enriched for deleterious de novo mutations in intellectual disabilities and autism spectrum disorder, but the causative molecular pathways are not fully known 1,2 . Synaptic activity in neurons is critical for learning and memory and proper neural development 3 . Neural activity prompts calcium influx and transcription within minutes, facilitated in the nucleus by various transcription factors (TFs) and chromatin modifiers 4 . While BAF is required for activity-dependent developmental processes such as dendritic outgrowth 5-7 , the immediate molecular consequences of neural activity on BAF complexes and their functions are unknown. Here we mapped minute-scale biochemical consequences of neural activity, modeled by membrane depolarization of embryonic mouse primary cortical neurons, on BAF complexes. We used acute chemical perturbations of BAF ATPase activity and kinase signaling to define the activity-dependent effects on BAF complexes and activity-dependent BAF functions. Our studies found that BAF complexes change in subunit composition and are selectively phosphorylated within 10 minutes of depolarization. Increased levels of the core PBAF subunit Baf200/ Arid2 , uniquely containing an RFX-like DNA-binding domain, are concurrent with ATPase-dependent opening of chromatin at RFX/X-box motifs. Changes in BAF composition and phosphorylation lead to the regulation of chromatin accessibility for critical neurogenesis TFs. These biochemical effects are a convergent phenomenon downstream of multiple growth factor signaling pathways in mouse neurons and fibroblasts suggesting that BAF integrates signaling information from the membrane. In support of such a membrane-to-nucleus signaling cascade, we also identified a BAF-interacting kinase, Dclk2, whose inhibition attenuates BAF phosphorylation selectively. Our findings support a direct role of BAF complexes in responding to synaptic activity to regulate TF binding and transcription.

Large spin-orbit coupling and helical spin textures in 2D heterostructure [Pb2BiS3][AuTe2].

Two-dimensional heterostructures with strong spin-orbit coupling have direct relevance to topological quantum materials and potential applications in spin-orbitronics. In this work, we report on novel quantum phenomena in [Pb2BiS3][AuTe2], a new 2D strong spin-orbit coupling heterostructure system. Transport measurements reveal the spin-related carrier scattering is at odds with the Abrikosov-Gorkov model due to strong spin-orbit coupling. This is consistent with our band structure calculations which reveal a large spin-orbit coupling gap of εso = 0.21 eV. The band structure is also characterized by helical-like spin textures which are mainly induced by strong spin-orbit coupling and the inversion symmetry breaking in the heterostructure system.

Temperature-Dependent Three-Dimensional Anisotropy of the Magnetoresistance in WTe_{2}.

Extremely large magnetoresistance (XMR) was recently discovered in WTe_{2}, triggering extensive research on this material regarding the XMR origin. Since WTe_{2} is a layered compound with metal layers sandwiched between adjacent insulating chalcogenide layers, this material has been considered to be electronically two-dimensional (2D). Here we report two new findings on WTe_{2}: (1) WTe_{2} is electronically 3D with a mass anisotropy as low as 2, as revealed by the 3D scaling behavior of the resistance R(H,θ)=R(ϵ_{θ}H) with ϵ_{θ}=(cos^{2}θ+γ^{-2}sin^{2}θ)^{1/2}, θ being the magnetic field angle with respect to the c axis of the crystal and γ being the mass anisotropy and (2) the mass anisotropy γ varies with temperature and follows the magnetoresistance behavior of the Fermi liquid state. Our results not only provide a general scaling approach for the anisotropic magnetoresistance but also are crucial for correctly understanding the electronic properties of WTe_{2}, including the origin of the remarkable "turn-on" behavior in the resistance versus temperature curve, which has been widely observed in many materials and assumed to be a metal-insulator transition.

A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab.

Belimumab is a monoclonal antibody against soluble B-lymphocyte stimulator, an essential growth factor for B-cell maturation and activation, which was approved by the US FDA in 2011 for patients with active autoantibody-positive systemic lupus erythematosus (SLE) who have failed standard treatment. Here we present the case of a 40-year-old woman with SLE diagnosed with progressive multifocal leukoencephalopathy (PML) on belimumab. After a total of 10 infusions of belimumab, from August 2012 through April 2013, in April 2013 she developed progressive neurologic decline with episodic dystonia and autonomic symptoms. Her imaging showed multifocal, confluent regions of T2 hyperintensity in the white matter bilaterally, and CSF JCV PCR returned positive. Based on the patient's clinically mild SLE and the timing of symptom onset, belimumab likely played a key role in the development of PML. Trials of belimumab for other autoimmune diseases are ongoing; as applications for this novel drug broaden, careful monitoring for this potentially fatal adverse effect is warranted.

Huge critical current density and tailored superconducting anisotropy in SmFeAsO0.8F0.15 by low-density columnar-defect incorporation.

Iron-based superconductors could be useful for electricity distribution and superconducting magnet applications because of their relatively high critical current densities and upper critical fields. SmFeAsO0.8F0.15 is of particular interest as it has the highest transition temperature among these materials. Here we show that by introducing a low density of correlated nano-scale defects into this material by heavy-ion irradiation, we can increase its critical current density to up to 2 × 107 A cm⁻² at 5 K--the highest ever reported for an iron-based superconductor--without reducing its critical temperature of 50 K. We also observe a notable reduction in the thermodynamic superconducting anisotropy, from 8 to 4 upon irradiation. We develop a model based on anisotropic electron scattering that predicts that the superconducting anisotropy can be tailored via correlated defects in semimetallic, fully gapped type II superconductors.

Catalyst-free growth of millimeter-long topological insulator Bi2Se3 nanoribbons and the observation of the π-Berry phase.

We report the growth of single-crystalline Bi(2)Se(3) nanoribbons with lengths up to several millimeters via a catalyst-free physical vapor deposition method. Scanning transmission electron microscopy analysis reveals that the nanoribbons grow along the (112̅0) direction. We obtain a detailed characterization of the electronic structure of the Bi(2)Se(3) nanoribbons from measurements of Shubnikov-de Haas (SdH) quantum oscillations. Angular dependent magneto-transport measurements reveal a dominant two-dimensional contribution originating from surface states. The catalyst-free synthesis yields high-purity nanocrystals enabling the observation of a large number of SdH oscillation periods and allowing for an accurate determination of the π-Berry phase, one of the key features of Dirac fermions in topological insulators. The long-length nanoribbons open the possibility for fabricating multiple nanoelectronic devices on a single nanoribbon.

'Nature-inspired' drug-protein complexes as inhibitors of Abeta aggregation.

Protein-protein interactions are a regulatory mechanism for a number of physiological and pathological cellular processes. Neurodegenerative diseases, such as AD (Alzheimer's disease), are associated with the accelerated production or delayed clearance of protein aggregates. Hence, inhibition of pathologic protein-protein interactions is a very attractive mechanism for drug development. This review focuses on a novel therapeutic strategy to inhibit the de novo formation of protein aggregates. Inspired by strategies used in Nature and optimized over millions of years of evolution, we have created a bifunctional molecule [SLF (synthetic ligand for FK506-binding protein)-CR (Congo Red)] that is able to block Abeta (amyloid beta) aggregation by borrowing the surface and steric bulk of a cellular chaperone.

Nanowires and nanoribbons of charge-density-wave conductor NbSe3.

We report synthesis of nanowires and nanoribbons of the charge-density-wave conductor NbSe(3) through direct reaction of Nb and Se powders. The transverse dimension of the obtained nanostructures, as identified with scanning/transmission electron microscopy, ranges from 20 to 700 nm. X-ray and selected area electron diffraction analyses indicate that these nanowires and nanoribbons are single crystalline. Four-probe resistivity measurements confirm the expected charge-density-wave transitions, and furthermore, we find significant enhancement in the depinning threshold fields, which we attribute to a confinement effect.

Crystal-lattice coupling to the vortex-melting transition in YBa(2)Cu(3)O(7-delta).

Distinct discontinuities in the thermal expansion of the crystal lattice are observed at the melting transition of the vortex lattice in a naturally untwinned reversible YBa(2)Cu3O(7-delta) single crystal using high-resolution dilatometry. This coupling between the vortex transition and the crystal lattice demonstrates that the crystal lattice is more than a mere host for the vortices, and it is attributed to a strong pressure dependence of the superconducting transition temperature and thus to the condensation energy at the vortex-melting temperature.

Two-band superconductivity in MgB2.

The study of the anisotropic superconductor MgB2 using a combination of scanning tunneling microscopy and spectroscopy reveals two distinct energy gaps at Delta(1)=2.3 meV and Delta(2)=7.1 meV at 4.2 K. Different spectral weights of the partial superconducting density of states are a reflection of different tunneling directions in this multiband system. Temperature evolution of the tunneling spectra follows the BCS scenario [Phys. Rev. Lett. 3, 552 (1959)]] with both gaps vanishing at the bulk T(c). The data confirm the importance of Fermi-surface sheet dependent superconductivity in MgB2 proposed in the multigap model by Liu et al. [Phys. Rev. Lett. 87, 087005 (2001)]].

Vortex configurations, matching, and domain structure in large arrays of artificial pinning centers.

High-resolution scanning Hall probe microscopy has been used to image vortex configurations in very large periodic arrays of artificial pinning sites. Strong matching effects are seen at fields where either one or two vortices can sit at a site; with three vortices per site, however, no clear matching is observed. Matching effects have also been observed at several fractional multiples of the matching field, including 1/5, 1/4, 1/3, 1/2, and 3/4. These fractional values are characterized by striking domain structure and grain boundaries.

NFAT signaling in vertebrate development.

NFATc proteins transduce Ca(2+) signals to the nucleus and then pair with other proteins on DNA to generate NFAT complexes that activate transcription in response to both electrical and tyrosine kinase signaling. The four NFATc genes arose at the origin of vertebrates, implying that they have evolved for the development of vertebrate-specific functions, such as a complex nervous system, a recombinational immune system, and a vascular system with a complex heart. These speculations are borne out by studies of mice with null mutations in the different family members.

Signals transduced by Ca(2+)/calcineurin and NFATc3/c4 pattern the developing vasculature.

Vascular development requires an orderly exchange of signals between growing vessels and their supporting tissues, but little is known of the intracellular signaling pathways underlying this communication. We find that mice with disruptions of both NFATc4 and the related NFATc3 genes die around E11 with generalized defects in vessel assembly as well as excessive and disorganized growth of vessels into the neural tube and somites. Since calcineurin is thought to control nuclear localization of NFATc proteins, we introduced a mutation into the calcineurin B gene that prevents phosphatase activation by Ca(2+) signals. These CnB mutant mice exhibit vascular developmental abnormalities similar to the NFATc3/c4 null mice. We show that calcineurin function is transiently required between E7.5 and E8.5. Hence, early calcineurin/NFAT signaling initiates the later cross-talk between vessels and surrounding tissues that pattern the vasculature.

Cell signaling can direct either binary or graded transcriptional responses.

Transcriptional control is generally thought to operate as a binary switch, a behavior that might explain observations such as monoallelic gene expression, stochastic phenotypic changes and bimodal gene activation kinetics. By measuring the activity of the single-copy GAL1 promoter in single cells, we found that changes in the activities of either the transcriptional activator, Gal4 (by simple recruitment with synthetic ligands), or the transcriptional repressor, Mig1, generated graded (non-binary) changes in gene expression that were proportional to signal intensity. However, in the context of the endogenous glucose-responsive signaling pathway, these transcription factors formed part of a binary transcriptional response. Genetic studies demonstrated that this binary response resulted from regulation of a second repressor, Gal80, whereas regulation of Mig1 by a distinct signaling pathway generated graded changes in GAL1 promoter activity. Surprisingly, isogenetic cells can respond to glucose with either binary or graded changes in gene expression, depending on growth conditions. Our studies demonstrate that a given promoter can adapt either binary or graded behavior, and identify the Mig1 and Gal80 genes as necessary for binary versus graded behavior of the Gal1 promoter.

Dynamics of electrostatically driven granular media: effects of humidity.

We performed experimental studies of the effect of humidity on the dynamics of electrostatically driven granular materials. Both conducting and dielectric particles undergo a phase transition from an immobile state (granular solid) to a fluidized state (granular gas) with increasing applied field. Spontaneous precipitation of solid clusters from the gas phase occurs as the external driving is decreased. The clustering dynamics in conducting particles is primarily controlled by screening of the electric field but is aided by cohesion due to humidity. It is shown that humidity effects dominate the clustering process with dielectric particles.

Monitoring the duration of antigen-receptor occupancy by calcineurin/glycogen-synthase-kinase-3 control of NF-AT nuclear shuttling.

Recent structural studies have supported a kinetic model of TCR activation, raising the question of how the duration of receptor occupancy is translated into activation of immune response genes. We summarize evidence that the cytoplasmic-to-nuclear shuttling of NF-ATc family members monitors the duration of receptor occupancy.

An unusual phase transition to a second liquid vortex phase in the superconductor YBa2Cu3O7.

A magnetic field penetrates a superconductor through an array of 'vortices', each of which carries one quantum of flux that is surrounded by a circulating supercurrent. In this vortex state, the resistivity is determined by the dynamical properties of the vortex 'matter'. For the high-temperature copper oxide superconductors (see ref.1 for a theoretical review), the vortex phase can be a 'solid', in which the vortices are pinned, but the solid can 'melt' into a 'liquid' phase, in which their mobility gives rise to a finite resistance. (This melting phenomenon is also believed to occur in conventional superconductors, but in an experimentally inaccessible part of the phase diagram.) For the case of YBa2Cu3O7, there are indications of the existence of a critical point, at which the character of the melting changes. But neither the thermodynamic nature of the melting, nor the phase diagram in the vicinity of the critical point, has been well established. Here we report measurements of specific heat and magnetization that determine the phase diagram in this material to 26 T, well above the critical point. Our results reveal the presence of a reversible second-order transition above the critical point. An unusual feature of this transition-namely, that the high-temperature phase is the less symmetric in the sense of the Landau theory-is in accord with theoretical predictions of a transition to a second vortex-liquid phase.

Scanning tunneling spectroscopy in MgB2.

We present scanning tunneling microscopy measurements of the surface of superconducting MgB2 with a critical temperature of 39 K. In zero magnetic field the conductance spectra can be analyzed in terms of the standard BCS theory with a smearing parameter gamma. The value of the superconducting gap is 5 meV at 4.2 K, with no experimentally significant variation across the surface of the sample. The temperature dependence of the gap follows the BCS form, fully consistent with phonon-mediated superconductivity in this novel superconductor. The application of a magnetic field induces strong pair breaking as seen in the conductance spectra in fields up to 6 T.

Field induced biquadratic exchange in hard/soft ferromagnetic bilayers.

The appearance of biquadratic exchange coupling between soft Fe and hard SmCo thin layers is found. The remanent magnetization in the Fe layer reorients from parallel to perpendicular with respect to the SmCo easy axis after application of large enough negative field. To explain such an unexpected behavior in contacting ferromagnetic layers a model is proposed based on Slonczewski's fluctuating exchange mechanism. In our samples a partial remagnetization of the hard layer creates fluctuations of the bilinear interactions. The intralayer exchange averaging of the resulting magnetization fluctuations in the soft layer causes the observed biquadratic coupling.