RyR1-targeted drug discovery pipeline integrating FRET-based high-throughput screening and human myofiber dynamic Ca2+ assays.

Elevated cytoplasmic [Ca2+] is characteristic in severe skeletal and cardiac myopathies, diabetes, and neurodegeneration, and partly results from increased Ca2+ leak from sarcoplasmic reticulum stores via dysregulated ryanodine receptor (RyR) channels. Consequently, RyR is recognized as a high-value target for drug discovery to treat such pathologies. Using a FRET-based high-throughput screening assay that we previously reported, we identified small-molecule compounds that modulate the skeletal muscle channel isoform (RyR1) interaction with calmodulin and FK506 binding protein 12.6. Two such compounds, chloroxine and myricetin, increase FRET and inhibit [3H]ryanodine binding to RyR1 at nanomolar Ca2+. Both compounds also decrease RyR1 Ca2+ leak in human skinned skeletal muscle fibers. Furthermore, we identified compound concentrations that reduced leak by > 50% but only slightly affected Ca2+ release in excitation-contraction coupling, which is essential for normal muscle contraction. This report demonstrates a pipeline that effectively filters small-molecule RyR1 modulators towards clinical relevance

Collisions of particles in locally AdS spacetimes II Moduli of globally hyperbolic spaces

We investigate 3-dimensional globally hyperbolic AdS manifolds containing "particles", i.e., cone singularities of angles less than $2\pi$ along a time-like graph $\Gamma$. To each such space we associate a graph and a finite family of pairs of hyperbolic surfaces with cone singularities. We show that this data is sufficient to recover the space locally (i.e., in the neighborhood of a fixed metric). This is a partial extension of a result of Mess for non-singular globally hyperbolic AdS manifolds.Comment: 29 pages, 3 figures. v2: 41 pages, improved exposition. To appear, Comm. Math. Phys. arXiv admin note: text overlap with arXiv:0905.182

Microwave Electronics

Contains reports on three research projects.Office of Naval Research (Contract Nonr 1841(05)Purchase Order DDL-B15

Microwave Electronics

Contains research objectives and reports on three research projects.Department of the ArmyDepartment of the NavyDepartment of the Air Force under Contract AF19(122)-458U. S. Navy (Office of Naval Research) under Contract Nonr-1841(49)Lincoln Laboratory, Purchase Order DDL-B22

Microwave Electronics

Contains reports on five research projects

Harmonic fields on the extended projective disc and a problem in optics

The Hodge equations for 1-forms are studied on Beltrami's projective disc model for hyperbolic space. Ideal points lying beyond projective infinity arise naturally in both the geometric and analytic arguments. An existence theorem for weakly harmonic 1-fields, changing type on the unit circle, is derived under Dirichlet conditions imposed on the non-characteristic portion of the boundary. A similar system arises in the analysis of wave motion near a caustic. A class of elliptic-hyperbolic boundary-value problems is formulated for those equations as well. For both classes of boundary-value problems, an arbitrarily small lower-order perturbation of the equations is shown to yield solutions which are strong in the sense of Friedrichs.Comment: 30 pages; Section 3.3 has been revise

Perpendicular momentum injection by lower hybrid wave in a tokamak

The injection of lower hybrid waves for current drive into a tokamak affects the profile of intrinsic rotation. In this article, the momentum deposition by the lower hybrid wave on the electrons is studied. Due to the increase in the poloidal momentum of the wave as it propagates into the tokamak, the parallel momentum of the wave increases considerably. The change of the perpendicular momentum of the wave is such that the toroidal angular momentum of the wave is conserved. If the perpendicular momentum transfer via electron Landau damping is ignored, the transfer of the toroidal angular momentum to the plasma will be larger than the injected toroidal angular momentum. A proper quasilinear treatment proves that both perpendicular and parallel momentum are transferred to the electrons. The toroidal angular momentum of the electrons is then transferred to the ions via different mechanisms for the parallel and perpendicular momentum. The perpendicular momentum is transferred to ions through an outward radial electron pinch, while the parallel momentum is transferred through collisions.Comment: 22 pages, 4 figure

Plasma Physics

Contains reports on seven research projects.United States Atomic Energy Commission under Contract AT(30-1)-1842Joint Services Electronics Programs (U.S. Army, U.S. Navy, and U.S. Air Force) under Contract DA 28-043-AMC-02536(E

Microwave Electronics

Contains reports on two research projects

On the injectivity of the circular Radon transform arising in thermoacoustic tomography

The circular Radon transform integrates a function over the set of all spheres with a given set of centers. The problem of injectivity of this transform (as well as inversion formulas, range descriptions, etc.) arises in many fields from approximation theory to integral geometry, to inverse problems for PDEs, and recently to newly developing types of tomography. The article discusses known and provides new results that one can obtain by methods that essentially involve only the finite speed of propagation and domain dependence for the wave equation.Comment: To appear in Inverse Problem