Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics

Background and Purpose Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies. Experimental Approach We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca2+i) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression. Key Results Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca2+i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G670E). Conclusions and Implications The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses

Distributed phase-covariant cloning with atomic ensembles via quantum Zeno dynamics

We propose an interesting scheme for distributed orbital state quantum cloning with atomic ensembles based on the quantum Zeno dynamics. These atomic ensembles which consist of identical three-level atoms are trapped in distant cavities connected by a single-mode integrated optical star coupler. These qubits can be manipulated through appropriate modulation of the coupling constants between atomic ensemble and classical field, and the cavity decay can be largely suppressed as the number of atoms in the ensemble qubits increases. The fidelity of each cloned qubit can be obtained with analytic result. The present scheme provides a new way to construct the quantum communication network.Comment: 5 pages, 4 figure

Strings on conifolds from strong coupling dynamics, part I

A method to solve various aspects of the strong coupling expansion of the superconformal field theory duals of AdS_5 x X geometries from first principles is proposed. The main idea is that at strong coupling the configurations that dominate the low energy dynamics of the field theory compactified on a three sphere are given by certain non-trivial semi-classical configurations in the moduli space of vacua. We show that this approach is self-consistent and permits one to express most of the dynamics in terms of an effective N=4 SYM dynamics. This has the advantage that some degrees of freedom that move the configurations away from moduli space can be treated perturbatively, unifying the essential low energy dynamics of all of these theories. We show that with this formalism one can compute the energies of strings in the BMN limit in the Klebanov-Witten theory from field theory considerations, matching the functional form of results found using AdS geometry. This paper also presents various other technical results for the semiclassical treatment of superconformal field theories.Comment: 52 pages, JHEP3 styl