The atomistic level structure for the activated human κ-opioid receptor bound to the full Gi protein and the MP1104 agonist

The kappa opioid receptor (κOR) is an important target for pain therapeutics to reduce depression and other harmful side effects of existing medications. The analgesic activity is mediated by κOR signaling through the adenylyl cyclase-inhibitory family of Gi protein. Here, we report the three-dimensional (3D) structure for the active state of human κOR complexed with both heterotrimeric Gi protein and MP1104 agonist. This structure resulted from long molecular dynamics (MD) and metadynamics (metaMD) simulations starting from the 3.1-Å X-ray structure of κOR–MP1104 after replacing the nanobody with the activated Gi protein and from the 3.5-Å cryo-EM structure of μOR–Gi complex after replacing the 168 missing residues. Using MD and metaMD we discovered interactions to the Gi protein with strong anchors to two intracellular loops and transmembrane helix 6 of the κOR. These anchors strengthen the binding, contributing to a contraction in the binding pocket but an expansion in the cytoplasmic region of κOR to accommodate G protein. These remarkable changes in κOR structure reveal that the anchors are essential for activation

Viable models with non-universal gaugino mediated supersymmetry breaking

Recently, extra dimensional SUSY GUT models have been proposed in which compactification of the extra dimension(s) leads to a breakdown of the gauge symmetry and/or supersymmetry. We examine a particular class of higher-dimensional models exhibiting supersymmetry and SU(5) or SO(10) GUT symmetry. SUSY breaking occurs on a hidden brane, and is communicated to the visible brane via gaugino mediation. Non-universal gaugino masses are developed at the compactification scale as a consequence of a restricted gauge symmetry on the hidden brane. In this case, the compactification scale is at or slightly below the GUT scale. We examine the parameter space of such models where gaugino masses are related due to a Pati-Salam symmetry on the hidden brane. We find limited but significant regions of model parameter space where a viable spectra of SUSY matter is generated. Our results are extended to the more general case of three independent gaugino masses; here we find that large parameter space regions open up for large values of the U(1) gaugino mass M_1. We also find the relic density of neutralinos for these models to be generally below expectations from cosmological observations, thus leaving room for hidden sector states to make up the bulk of cold dark matter. Finally, we evaluate the branching fraction BF(b -> s gamma) and muon anomalous magnetic moment a_\mu.Comment: 21 pages, 9 figure

Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor

Agonists to the μ-opioid G protein-coupled receptor (μOR) can alleviate pain through activation of G protein signaling, but they can also induce β-arrestin activation, leading to such side effects as respiratory depression. Biased ligands to μOR that induce G protein signaling without inducing β-arrestin signaling can alleviate pain while reducing side effects. However, the mechanism for stimulating β-arrestin signaling is not known, making it difficult to design optimum biased ligands. We use extensive molecular dynamics simulations to determine three-dimensional (3D) structures of activated β-arrestin2 stabilized by phosphorylated μOR bound to the morphine and D-Ala², N-MePhe⁴, Gly-ol]-enkephalin (DAMGO) nonbiased agonists and to the TRV130 biased agonist. For nonbiased agonists, we find that the β-arrestin2 couples to the phosphorylated μOR by forming strong polar interactions with intracellular loop 2 (ICL2) and either the ICL3 or cytoplasmic region of transmembrane (TM6). Strikingly, Gi protein makes identical strong bonds with these same ICLs. Thus, the Gi protein and β-arrestin2 compete for the same binding site even though their recruitment leads to much different outcomes. On the other hand, we find that TRV130 has a greater tendency to bind the extracellular portion of TM2 and TM3, which repositions TM6 in the cytoplasmic region of μOR, hindering β-arrestin2 from making polar anchors to the ICL3 or to the cytosolic end of TM6. This dramatically reduces the affinity between μOR and β-arrestin2

Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor

Agonists to the μ-opioid G protein-coupled receptor (μOR) can alleviate pain through activation of G protein signaling, but they can also induce β-arrestin activation, leading to such side effects as respiratory depression. Biased ligands to μOR that induce G protein signaling without inducing β-arrestin signaling can alleviate pain while reducing side effects. However, the mechanism for stimulating β-arrestin signaling is not known, making it difficult to design optimum biased ligands. We use extensive molecular dynamics simulations to determine three-dimensional (3D) structures of activated β-arrestin2 stabilized by phosphorylated μOR bound to the morphine and D-Ala², N-MePhe⁴, Gly-ol]-enkephalin (DAMGO) nonbiased agonists and to the TRV130 biased agonist. For nonbiased agonists, we find that the β-arrestin2 couples to the phosphorylated μOR by forming strong polar interactions with intracellular loop 2 (ICL2) and either the ICL3 or cytoplasmic region of transmembrane (TM6). Strikingly, Gi protein makes identical strong bonds with these same ICLs. Thus, the Gi protein and β-arrestin2 compete for the same binding site even though their recruitment leads to much different outcomes. On the other hand, we find that TRV130 has a greater tendency to bind the extracellular portion of TM2 and TM3, which repositions TM6 in the cytoplasmic region of μOR, hindering β-arrestin2 from making polar anchors to the ICL3 or to the cytosolic end of TM6. This dramatically reduces the affinity between μOR and β-arrestin2

The atomistic level structure for the activated human κ-opioid receptor bound to the full Gi protein and the MP1104 agonist

The kappa opioid receptor (κOR) is an important target for pain therapeutics to reduce depression and other harmful side effects of existing medications. The analgesic activity is mediated by κOR signaling through the adenylyl cyclase-inhibitory family of Gi protein. Here, we report the three-dimensional (3D) structure for the active state of human κOR complexed with both heterotrimeric Gi protein and MP1104 agonist. This structure resulted from long molecular dynamics (MD) and metadynamics (metaMD) simulations starting from the 3.1-Å X-ray structure of κOR–MP1104 after replacing the nanobody with the activated Gi protein and from the 3.5-Å cryo-EM structure of μOR–Gi complex after replacing the 168 missing residues. Using MD and metaMD we discovered interactions to the Gi protein with strong anchors to two intracellular loops and transmembrane helix 6 of the κOR. These anchors strengthen the binding, contributing to a contraction in the binding pocket but an expansion in the cytoplasmic region of κOR to accommodate G protein. These remarkable changes in κOR structure reveal that the anchors are essential for activation

Studying the tendency of citizens to participate in the protection and development of land scape in Tehran

Today, as an essential part and parcel of urban landscape that they play a major role in metabolism and create a lack of serious damage to urban life. This study performed to investigate the willingness of citizens to participate in activities to protect and develop landscapeof Tehran district 4. The research was descriptive and correlation method that is used for collecting information. The statistical population consisted of district 4 of Tehran. The sample size was determined 230 by using Cochrane method. A questionnaire was used to collect data. According to the research, 63.04 percent of citizens showed participation in a high level. Among the variables investigated how citizen participation in conservation and development of landscape, effective strategies to motivate citizens to participate,the reasons for lack of cooperation and participation of citizens learn about gardening and landscaping,introductory training centers with the desire of citizens to participate in municipal plants open landscape had a significant relationship and stepwise regression analysis results showed that four variableseffective strategies to motivate citizens to participate,method to involve citizens in the landscape,the reasons for lack of cooperation and participation of citizens familiar with gardening and landscaping activities have on the willingness of citizens to participate effectively

What is the right theory for Anderson localization of light?

Anderson localization of light is traditionally described in analogy to electrons in a random potential. Within this description the disorder strength -- and hence the localization characteristics -- depends strongly on the wavelength of the incident light. In an alternative description in analogy to sound waves in a material with spatially fluctuating elastic moduli this is not the case. Here, we report on an experimentum crucis in order to investigate the validity of the two conflicting theories using transverse-localized optical devices. We do not find any dependence of the observed localization radii on the light wavelength. We conclude that the modulus-type description is the correct one and not the potential-type one. We corroborate this by showing that in the derivation of the traditional, potential-type theory a term in the wave equation has been tacititly neglected. In our new modulus-type theory the wave equation is exact. We check the consistency of the new theory with our data using a field-theoretical approach (nonlinear sigma model)

Permeation of CO₂ and N₂ through glassy poly(dimethyl phenylene) oxide under steady- and presteady-state conditions

Glassy polymers are often used for gas separations because of their high selectivity. Although the dual‐mode permeation model correctly fits their sorption and permeation isotherms, its physical interpretation is disputed, and it does not describe permeation far from steady state, a condition expected when separations involve intermittent renewable energy sources. To develop a more comprehensive permeation model, we combine experiment, molecular dynamics, and multiscale reaction–diffusion modeling to characterize the time‐dependent permeation of N₂ and CO₂ through a glassy poly(dimethyl phenylene oxide) membrane, a model system. Simulations of experimental time‐dependent permeation data for both gases in the presteady‐state and steady‐state regimes show that both single‐ and dual‐mode reaction–diffusion models reproduce the experimental observations, and that sorbed gas concentrations lag the external pressure rise. The results point to environment‐sensitive diffusion coefficients as a vital characteristic of transport in glassy polymers

Diagnosing Spin at the LHC via Vector Boson Fusion

We propose a new technique for determining the spin of new massive particles that might be discovered at the Large Hadron Collider. The method relies on pair-production of the new particles in a kinematic regime where the vector boson fusion production mechanism is enhanced. For this regime, we show that the distribution of the leading jets as a function of their relative azimuthal angle can be used to distinguish spin-0 from spin-1/2 particles. We illustrate this effect by considering the particular cases of (i) strongly-interacting, stable particles and (ii) supersymmetric particles carrying color charge. We argue that this method should be applicable in a wide range of new physics scenarios.Comment: 5 pages, 4 figure

Coisotropic D-branes on AdS4 x CP3 and massive deformations

We scan for massive type IIA SU(3)-structure compactifications of the type AdS4 x CP3 with internal symmetry group SO(4). This group acts on CP3 with cohomogeneity one, so that one would expect new non-homogeneous solutions. We find however that all such solutions enhance their symmetry group to Sp(2) and form, in fact, the homogeneous family first described in arXiv:0712.1396. This is in accordance with arXiv:0901.0969, which argues from the CFT-side that although new vacua with SO(4) symmetry group and N=2 supersymmetry should exist, they fall outside our ansatz of strict SU(3)-structure, and instead have genuine SU(3)x SU(3)-structure. We do find that the SO(4)-invariant description, which singles out one preferential direction in the internal space, is well-adapted for describing the embedding of AdS4-filling supersymmetric D8-branes on both the original ABJM configuration as its massive Sp(2)-symmetric deformations.Supersymmetry requires these D-branes to be of the coisotropic type, which means in particular that their world-volume gauge field must be non-trivial.Comment: 24 pages, 1 figure, v2: due to a serious mistake the claims of the paper had to be correcte