Identification of Gain and Loss of Function Missense Variants in MRGPRX2’s Transmembrane and Intracellular Domains for Mast Cell Activation by Substance p

The neuropeptide substance P (SP) contributes to neurogenic inflammation through the activation of human mast cells via Mas-related G protein-coupled receptor-X2 (MRGPRX2). Using pertussis toxins and YM-254890, we demonstrated that SP induces Ca2+ mobilization and degranulation via both the Gαi and Gαq family of G proteins in rat basophilic leukemia (RBL-2H3)cells stably expressing MRGPRX2. To determine the roles of MRGPRX2’s transmembrane (TM) and intracellular domains on SP-induced responses, we utilized information obtained from both structural modeling and naturally occurring MRGPRX2 missense variants. We found that highly conservedresidues in TM6 (I225) and TM7 (Y279) of MRGPRX2 are essential for SP-induced Ca2+ mobilization and degranulation in transiently transfected RBL-2H3 cells. Cells expressing missense variants in the receptor’s conserved residues (V123F and V282M) as well as intracellular loops (R138C andR141C) failed to respond to SP. By contrast, replacement of all five Ser/Thr residues with Ala and missense variants (S325L and L329Q) in MRGPRX2’s carboxyl-terminus resulted in enhanced mast cell activation by SP when compared to the wild-type receptor. These findings suggest that MRGPRX2utilizes conserved residues in its TM domains and intracellular loops for coupling to G proteins and likely undergoes desensitization via phosphorylation at Ser/Thr residues in its carboxyl-terminus. Furthermore, identification of gain and loss of function MRGPRX2 variants has important clinical implications for SP-mediated neurogenic inflammation and other chronic inflammatory diseases

Mrgprx2 Activation by Rocuronium: Insights From Studies with Human Skin Mast Cells and Missense Variants

Perioperative hypersensitivity (POH) to the neuromuscular blocking drug (NMBD) rocuronium was previously thought to be IgE and mast cell (MC)-mediated. However, the recent seminalobservation that rocuronium induces degranulation in murine peritoneal MCs (PMCs) via Mas-related G protein-coupled receptor B2 (MrgprB2) led to the idea that POH to this drug involves the activation of MRGPRX2 (human ortholog of MrgprB2). Furthermore, based on the demonstration that a patient with POH to rocuronium displayed three missense mutations (M196I, L226P and L237P) in MRGPRX2’s transmembrane domains, it was proposed that this hypersensitivity reaction resulted from aberrant activation of this receptor. We found that rocuronium at 20 μg/mL causeddegranulation in mouse PMCs via MrgprB2 but required at least 500 μg/mL to induce degranulation in human MCs via MRGPRX2. Furthermore, RBL-2H3 cells transiently expressing M196I, L226P and L237P variants did not display enhanced degranulation in response to rocuronium when comparedto the wild-type receptor. These findings provide the first demonstration that rocuronium induces degranulation in human MCs via MRGPRX2. Furthermore, the important differences between Mrg-prB2 and MRGPRX2 and the inability of rocuronium to induce enhanced response in cells expressing MRGPRX2 variants suggest that the mechanism of its POH is more complex than previously thought

Bell-inequality violation with "thermal" radiation

The model of a quantum-optical device for a conditional preparation of entangled states from input mixed states is presented. It is demonstrated that even thermal or pseudo-thermal radiation can be entangled in such a way, that Bell-inequalities are violated

Coherent states for exactly solvable potentials

A general algebraic procedure for constructing coherent states of a wide class of exactly solvable potentials e.g., Morse and P{\"o}schl-Teller, is given. The method, {\it a priori}, is potential independent and connects with earlier developed ones, including the oscillator based approaches for coherent states and their generalizations. This approach can be straightforwardly extended to construct more general coherent states for the quantum mechanical potential problems, like the nonlinear coherent states for the oscillators. The time evolution properties of some of these coherent states, show revival and fractional revival, as manifested in the autocorrelation functions, as well as, in the quantum carpet structures.Comment: 11 pages, 4 eps figures, uses graphicx packag

Astrophysical structures from primordial quantum black holes

The characteristic sizes of astrophysical structures, up to the whole observed Universe, can be recovered, in principle, assuming that gravity is the overall interaction assembling systems starting from microscopic scales, whose order of magnitude is ruled by the Planck length and the related Compton wavelength. This result agrees with the absence of screening mechanisms for the gravitational interaction and could be connected to the presence of Yukawa corrections in the Newtonian potential which introduce typical interaction lengths. This result directly comes out from quantization of primordial black holes and then characteristic interaction lengths directly emerge from quantum field theory.Comment: 11 page

Cytokine treatment optimises the immunotherapeutic effects of umbilical cord-derived MSC for treatment of inflammatory liver disease

Background: Mesenchymal stromal cells (MSC) possess immunomodulatory properties and low immunogenicity, both crucial properties for their development into an effective cellular immunotherapy. They have shown benefit in clinical trials targeting liver diseases; however the efficacy of MSC therapy will benefit from improvement of the immunomodulatory and immunogenic properties of MSC. Methods: MSC derived from human umbilical cords (ucMSC) were treated for 3 days in vitro with various inflammatory factors, interleukins, vitamins and serum deprivation. Their immunogenicity and immunomodulatory capacity were examined by gene-expression analysis, surface-marker expressions, IDO activity, PGE2 secretion and inhibition of T cell proliferation and IFNγ production. Furthermore, their activation of NK cell cytotoxicity was investigated via CD107a expre

Geometry and material effects in Casimir physics - Scattering theory

We give a comprehensive presentation of methods for calculating the Casimir force to arbitrary accuracy, for any number of objects, arbitrary shapes, susceptibility functions, and separations. The technique is applicable to objects immersed in media other than vacuum, to nonzero temperatures, and to spatial arrangements in which one object is enclosed in another. Our method combines each object's classical electromagnetic scattering amplitude with universal translation matrices, which convert between the bases used to calculate scattering for each object, but are otherwise independent of the details of the individual objects. This approach, which combines methods of statistical physics and scattering theory, is well suited to analyze many diverse phenomena. We illustrate its power and versatility by a number of examples, which show how the interplay of geometry and material properties helps to understand and control Casimir forces. We also examine whether electrodynamic Casimir forces can lead to stable levitation. Neglecting permeabilities, we prove that any equilibrium position of objects subject to such forces is unstable if the permittivities of all objects are higher or lower than that of the enveloping medium; the former being the generic case for ordinary materials in vacuum.Comment: 44 pages, 11 figures, to appear in upcoming Lecture Notes in Physics volume in Casimir physic

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

Synchronization of coupled limit cycles

A unified approach for analyzing synchronization in coupled systems of autonomous differential equations is presented in this work. Through a careful analysis of the variational equation of the coupled system we establish a sufficient condition for synchronization in terms of the geometric properties of the local limit cycles and the coupling operator. This result applies to a large class of differential equation models in physics and biology. The stability analysis is complemented with a discussion of numerical simulations of a compartmental model of a neuron.Comment: Journal of Nonlinear Science, accepte