Redox regulation of type-I inositol trisphosphate receptors in intact mammalian cells.

A sensitization of inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ release is associated with oxidative stress in multiple cell types. These effects are thought to be mediated by alterations in the redox state of critical thiols in the IP3R, but this has not been directly demonstrated in intact cells. Here, we utilized a combination of gel-shift assays with MPEG-maleimides and LC-MS/MS to monitor the redox state of recombinant IP3R1 expressed in HEK293 cells. We found that under basal conditions, ∼5 of the 60 cysteines are oxidized in IP3R1. Cell treatment with 50 μm thimerosal altered gel shifts, indicating oxidation of ∼20 cysteines. By contrast, the shifts induced by 0.5 mm H2O2 or other oxidants were much smaller. Monitoring of biotin-maleimide attachment to IP3R1 by LC-MS/MS with 71% coverage of the receptor sequence revealed modification of two cytosolic (Cys-292 and Cys-1415) and two intraluminal cysteines (Cys-2496 and Cys-2533) under basal conditions. The thimerosal treatment modified an additional eleven cysteines, but only three (Cys-206, Cys-767, and Cys-1459) were consistently oxidized in multiple experiments. H2O2 also oxidized Cys-206 and additionally oxidized two residues not modified by thimerosal (Cys-214 and Cys-1397). Potentiation of IP3R channel function by oxidants was measured with cysteine variants transfected into a HEK293 IP3R triple-knockout cell line, indicating that the functionally relevant redox-sensitive cysteines are predominantly clustered within the N-terminal suppressor domain of IP3R. To our knowledge, this study is the first that has used proteomic methods to assess the redox state of individual thiols in IP3R in intact cells. © 2018 Joseph et al

P and T Violation From Certain Dimension Eight Weinberg Operators

Dimension eight operators of the Weinberg type have been shown to give important contributions to CP violating phenomena, such as the electric dipole moment of the neutron. In this note we show how operators related to these (and expected to occur on equal footing) can give rise to time-reversal violating phenomena such as atomic electric dipole moments. We also estimate the induced parity violating phenomena such as small ``wrong'' parity admixtures in atomic states and find that they are negligible. Uses harvmac.tex and epsf.tex; one figure submitted as a uuencoded, compressed EPS file.Comment: 6 pages, EFI-92-5

``GLUELUMP'' SPECTRUM AND ADJOINT SOURCE POTENTIAL IN LATTICE QCD3_3

We calculate the potential between ``quarks'' which are in the adjoint representation of SU(2) color in the three-dimensional lattice theory. We work in the scaling region of the theory and at large quark separations $R$. We also calculate the masses $M_{Qg}$ of color-singlet bound states formed by coupling an adjoint quark to adjoint glue (``gluelumps''). Good scaling behavior is found for the masses of both magnetic (angular momentum $J=0$) and electric ($J=1$) gluelumps, and the magnetic gluelump is found to be the lowest-lying state. It is naively expected that the potential for adjoint quarks should saturate above a separation $R_{\rm scr}$ where it becomes energetically favorable to produce a pair of gluelumps. We obtain a good estimate of the naive screening distance $R_{\rm scr}$. However we find little evidence of saturation in the potential out to separations $R$ of about twice $R_{\rm scr}$.Comment: 8 pages plus 8 figures in 2 postscript files (uuencoded

Tadpole-improved SU(2) lattice gauge theory

A comprehensive analysis of tadpole-improved SU(2) lattice gauge theory is made. Simulations are done on isotropic and anisotropic lattices, with and without improvement. Two tadpole renormalization schemes are employed, one using average plaquettes, the other using mean links in Landau gauge. Simulations are done with spatial lattice spacings $a_s$ in the range of about 0.1--0.4 fm. Results are presented for the static quark potential, the renormalized lattice anisotropy $a_t/a_s$ (where $a_t$ is the ``temporal'' lattice spacing), and for the scalar and tensor glueball masses. Tadpole improvement significantly reduces discretization errors in the static quark potential and in the scalar glueball mass, and results in very little renormalization of the bare anisotropy that is input to the action. We also find that tadpole improvement using mean links in Landau gauge results in smaller discretization errors in the scalar glueball mass (as well as in the static quark potential), compared to when average plaquettes are used. The possibility is also raised that further improvement in the scalar glueball mass may result when the coefficients of the operators which correct for discretization errors in the action are computed beyond tree level.Comment: 14 pages, 7 figures (minor changes to overall scales in Fig.1; typos removed from Eqs. (3),(4),(15); some rewording of Introduction

Janus Black Holes

In this paper Janus black holes in AdS3 are considered. These are static solutions of an Einstein-scalar system with broken translation symmetry along the horizon. These solutions are dual to interface conformal field theories at finite temperature. An approximate solution is first constructed using perturbation theory around a planar BTZ black hole. Numerical and exact solutions valid for all sets of parameters are then found and compared. Using the exact solution the thermodynamics of the system is analyzed. The entropy associated with the Janus black hole is calculated and it is found that the entropy of the black Janus is the sum of the undeformed black hole entropy and the entanglement entropy associated with the defect.Comment: 28 pages, 2 figures, reference adde

The (LATTICE) QCD Potential and Running Coupling: How to Accurately Interpolate between Multi-Loop QCD and the String Picture

We present a simple parameterization of a running coupling constant, defined via the static potential, that interpolates between 2-loop QCD in the UV and the string prediction in the IR. Besides the usual \Lam-parameter and the string tension, the coupling depends on one dimensionless parameter, determining how fast the crossover from UV to IR behavior occurs (in principle we know how to take into account any number of loops by adding more parameters). Using a new Ansatz for the LATTICE potential in terms of the continuum coupling, we can fit quenched and unquenched Monte Carlo results for the potential down to ONE lattice spacing, and at the same time extract the running coupling to high precision. We compare our Ansatz with 1-loop results for the lattice potential, and use the coupling from our fits to quantitatively check the accuracy of 2-loop evolution, compare with the Lepage-Mackenzie estimate of the coupling extracted from the plaquette, and determine Sommer's scale $r_0$ much more accurately than previously possible. For pure SU(3) we find that the coupling scales on the percent level for $\beta\geq 6$.Comment: 47 pages, incl. 4 figures in LaTeX [Added remarks on correlated vs. uncorrelated fits in sect. 4; corrected misprints; updated references.

CryoSIM: super-resolution 3D structured illumination cryogenic fluorescence microscopy for correlated ultrastructural imaging

Rapid cryopreservation of biological specimens is the gold standard for visualizing cellular structures in their true structural context. However, current commercial cryo-fluorescence microscopes are limited to low resolutions. To fill this gap, we have developed cryoSIM, a microscope for 3D super-resolution fluorescence cryo-imaging for correlation with cryo-electron microscopy or cryo-soft X-ray tomography. We provide the full instructions for replicating the instrument mostly from off-the-shelf components and accessible, user-friendly, open-source Python control software. Therefore, cryoSIM democratizes the ability to detect molecules using super-resolution fluorescence imaging of cryopreserved specimens for correlation with their cellular ultrastructure.Funding: Wellcome Trust (091911/Z/11/Z, 096144/Z/11/Z, 105605/Z/14/Z, 107457/Z/15/Z, 203141/Z/16/Z, 209412/Z/17/Z); H2020Marie Skłodowska-Curie Actions (700184)

Metabolic adaptation to the chronic loss of Ca 2+ signaling induced by KO of IP 3 receptors or the mitochondrial Ca 2+ uniporter

Calcium signaling is essential for regulating many biological processes. Endoplasmic reticulum inositol trisphosphate receptors (IP3Rs) and the mitochondrial Ca2+ uniporter (MCU) are key proteins that regulate intracellular Ca2+ concentration. Mitochondrial Ca2+ accumulation activates Ca2+-sensitive dehydrogenases of the tricarboxylic acid (TCA) cycle that maintain the biosynthetic and bioenergetic needs of both normal and cancer cells. However, the interplay between calcium signaling and metabolism is not well understood. In this study, we used human cancer cell lines (HEK293 and HeLa) with stable KOs of all three IP3R isoforms (triple KO [TKO]) or MCU to examine metabolic and bioenergetic responses to the chronic loss of cytosolic and/or mitochondrial Ca2+ signaling. Our results show that TKO cells (exhibiting total loss of Ca2+ signaling) are viable, displaying a lower proliferation and oxygen consumption rate, with no significant changes in ATP levels, even when made to rely solely on the TCA cycle for energy production. MCU KO cells also maintained normal ATP levels but showed increased proliferation, oxygen consumption, and metabolism of both glucose and glutamine. However, MCU KO cells were unable to maintain ATP levels and died when relying solely on the TCA cycle for energy. We conclude that constitutive Ca2+ signaling is dispensable for the bioenergetic needs of both IP3R TKO and MCU KO human cancer cells, likely because of adequate basal glycolytic and TCA cycle flux. However, in MCU KO cells, the higher energy expenditure associated with increased proliferation and oxygen consumption makes these cells more prone to bioenergetic failure under conditions of metabolic stress

Estimation of changes in the force of infection for intestinal and urogenital schistosomiasis in countries with Schistosomiasis Control Initiative-assisted programmes

The last decade has seen an expansion of national schistosomiasis control programmes in Africa based on large-scale preventative chemotherapy. In many areas this has resulted in considerable reductions in infection and morbidity levels in treated individuals. In this paper, we quantify changes in the force of infection (FOI), defined here as the per (human) host parasite establishment rate, to ascertain the impact on transmission of some of these programmes under the umbrella of the Schistosomiasis Control Initiative (SCI)

Lattice Calculation of Heavy-Light Decay Constants with Two Flavors of Dynamical Quarks

We present results for $f_B$, $f_{B_s}$, $f_D$, $f_{D_s}$ and their ratios in the presence of two flavors of light sea quarks ($N_f=2$). We use Wilson light valence quarks and Wilson and static heavy valence quarks; the sea quarks are simulated with staggered fermions. Additional quenched simulations with nonperturbatively improved clover fermions allow us to improve our control of the continuum extrapolation. For our central values the masses of the sea quarks are not extrapolated to the physical $u$, $d$ masses; that is, the central values are "partially quenched." A calculation using "fat-link clover" valence fermions is also discussed but is not included in our final results. We find, for example, $f_B = 190 (7) (^{+24}_{-17}) (^{+11}_{-2}) (^{+8}_{-0})$ MeV, $f_{B_s}/f_B = 1.16 (1) (2) (2) (^{+4}_{-0})$, $f_{D_s} = 241 (5) (^{+27}_{-26}) (^{+9}_{-4}) (^{+5}_{-0})$ MeV, and $f_{B}/f_{D_s} = 0.79 (2) (^{+5}_{-4}) (3) (^{+5}_{-0})$, where in each case the first error is statistical and the remaining three are systematic: the error within the partially quenched $N_f=2$ approximation, the error due to the missing strange sea quark and to partial quenching, and an estimate of the effects of chiral logarithms at small quark mass. The last error, though quite significant in decay constant ratios, appears to be smaller than has been recently suggested by Kronfeld and Ryan, and Yamada. We emphasize, however, that as in other lattice computations to date, the lattice $u,d$ quark masses are not very light and chiral log effects may not be fully under control.Comment: Revised version includes an attempt to estimate the effects of chiral logarithms at small quark mass; central values are unchanged but one more systematic error has been added. Sections III E and V D are completely new; some changes for clarity have also been made elsewhere. 82 pages; 32 figure