Supersymmetric solutions to Euclidean Romans supergravity

We study Euclidean Romans supergravity in six dimensions with a non-trivial Abelian R-symmetry gauge field. We show that supersymmetric solutions are in one-to-one correspondence with solutions to a set of differential constraints on an SU(2) structure. As an application of our results we (i) show that this structure reduces at a conformal boundary to the five-dimensional rigid supersymmetric geometry previously studied by the authors, (ii) find a general expression for the holographic dual of the VEV of a BPS Wilson loop, matching an exact field theory computation, (iii) construct holographic duals to squashed Sasaki-Einstein backgrounds, again matching to a field theory computation, and (iv) find new analytic solutions.Comment: 31 pages; v2: published version (with reference added

Supersymmetric gauge theories on squashed five-spheres and their gravity duals

We construct the gravity duals of large N supersymmetric gauge theories defined on squashed five-spheres with SU(3) x U(1) symmetry. These five-sphere backgrounds are continuously connected to the round sphere, and we find a one-parameter family of 3/4 BPS deformations and a two-parameter family of (generically) 1/4 BPS deformations. The gravity duals are constructed in Euclidean Romans F(4) gauged supergravity in six dimensions, and uplift to massive type IIA supergravity. We holographically renormalize the Romans theory, and use our general result to compute the renormalized on-shell actions for the solutions. The results agree perfectly with the large N limit of the dual gauge theory partition function, which we compute using large N matrix model techniques. In addition we compute BPS Wilson loops in these backgrounds, both in supergravity and in the large N matrix model, again finding precise agreement. Finally, we conjecture a general formula for the partition function on any five-sphere background, which for fixed gauge theory depends only on a certain supersymmetric Killing vector.Comment: 63 pages, no figures; v2: minor corrections and reference adde

Theodore Dreiser's Gloom and Estelle Bloom Kubitz's I and one of the others : an edition

Theodore Dreiser was one of the most important American writers from the period of 1900 to the 1930s. Of signal importance to understanding Dreiser’s life and works are the years he lived in Greenwich Village, 1914 to 1919. He left his wife, Sara, and established a bohemian life of extravagance and sexual adventure, forming simultaneous liaisons with dozens of women, most of whom seeking to establish their own literary careers. He shamelessly exploited their desire for mentorship by seducing them even as he employed them to type and edit his manuscripts. Estelle Bloom Kubitz was one of the most significant of these women and also one about whom little is known. That Kubitz was simultaneously in love with Dreiser and repelled by him is evident in letters to her sister and in an unpublished manuscript, “I and One of the Others,” where Dreiser appears as S.O.B. and Kubitz as Miss DamnPhool. Dreiser himself began an account of his relationship with Kubitz entitled “Gloom,” intending it to be part of his serialized novel “This Madness” (1929) but left it unfinished. This thesis is a biographical introduction to “Gloom” and “I and One of the Others.” Both texts advance an understanding of the Dreiser-Kubitz relationship by revealing Dreiser’s attraction to Kubitz and the effects his promiscuity had on her

Membrane Topology of Cytochrome P450 2B4 in Langmuir-Blodgett Monolayers

Using Langmuir–Blodgett monolayers of both phosphatidylethanolamines and phosphatidylcholines as membrane mimics, we have examined the topology of cytochrome P450 2B4 anchoring. The interaction of wild-type P450 2B4 with phosphatidylethanolamine monolayers can be characterized as a biphasic reaction, with the initial fast phase explained by the specific insertion of membrane-spanning segments of the protein into the monolayer. Injection of cytochrome b5 (b5) beneath dipalmitoyl-phosphatidylcholine monolayers also resulted in biphasic kinetics. Regardless of the nature of the lipid employed, neither a truncated cytochrome P450 2B4 (P450 2B4 &#x0394 2–27) lacking the amino-terminal hydrophobic residues widely believed to be the major transmembrane segment nor a soluble b5 fragment (&#x0394 b5) lacking its carboxy terminus anchor exhibit the fast-phase behavior characteristic of specific insertion. To further characterize the membrane topology of P450 2B4, its insertion area in DPPE monolayers was measured and analyzed with use of the Gibbs equation for adsorption at an interface. The mean molecular insertion area derived from isotherms of P450 2B4 in a DPPE monolayer at a pressure of 19 mN/m, 680 ± 95 Å2 is large enough to accommodate two to four transmembrane helices. The large insertion area and the fact that the truncated cytochrome retains as much as 30% of its membrane localization when expressed in Escherichia coli (Pernecky, S. J., Larson, J. R., Philpot, R.M., and Coon, M. J. (1993) Proc. Natl. Acad. Sci. USA 90, 2651–2655) suggest that this cytochrome is not deeply embedded but that other regions, in addition to the amino-terminal 26 residues, may be involved in the interaction of cytochrome P450 with the membrane

Defluorination of 4-fluorophenol by Cytochrome P450BM3-F87G: Activation by long Chain Fatty Aldehydes.

Cytochrome P450BM3-F87G catalyzed the oxidative defluorination of 4-fluorophenol, followed by reduction of the resulting benzoquinone to hydroquinone via the NADPH P450-reductase activity of the enzyme. The k catand K m for this reaction were 71 ± 5 min-1 and 9.5 ± 1.3 mM, respectively. Co-incubation of the reaction mixture with long chain aldehydes stimulated the defluorination reaction, with the 2,3-unsaturated aldehyde, 2-decenal producing a 12-fold increase in catalytic efficiency. At 150 µM aldehyde, k cat increased to 158 ± 4, while K m decreased to 1.8 ± 0.2. The effects of catalase, glutathione and ascorbate on the reaction were all consistent with a direct oxygen insertion mechanism, as opposed to a radical mechanism. The study demonstrates the potential use of P450BM3 mutants in oxidative defluorination reactions, and characterizes the novel stimulatory action of straight chain aldehydes on this activity

Effects of green tea extracts on gene expression in HepG2 and Cal-27 cells

Green tea extract is known to contain compounds that are able to produce antioxidant effects in many types of living cells. Treatment of cultured human hepatoma (HepG2) cells with green tea extract resulted in dramatically increased expression of at least 15 genes that are present on a commercial human drug metabolism gene array. RT-PCR was used to confirm the microarray results, and analysis of the 5'-flanking region of each of these genes revealed potential electrophile/antioxidant response elements. Members of the acetyl transferase, epoxide hydrolase, sulfotransferase and glutathione transferase gene families were strongly induced. In addition, the human tongue carcinoma cell line Cal-27 did not respond to green tea extract in the same way, as none of the induced genes in the HepG2 cells were induced in the Cal-27 cells. The lack of induction of detoxification enzymes in the Cal-27 cell line may help to explain the previously observed increased cytotoxicity of green tea catechins on this cell line

Cytochrome P450 expression and activities in rat, rabbit and bovine tongue

Xenobiotic metabolism in the tongue has received little attention in the literature. In the present study, we report a comparative analysis of constitutive cytochrome P450 (CYP) expression and activities in the tongue. First we compared catalytic activities of rabbit, rat and bovine tongue samples using the probe substrates 4-nitrophenol, 1-phenylethanol, caffeine and 7-ethoxycoumarin. Rabbit tongue samples showed the highest activities for all substrates. We then compared the activities in rat and rabbit tongue with those in the rabbit liver, along with the effects of P450 inhibitors on specific activities. Combined, the activity studies indicate that CYP1A1 is active in rabbit tongue cells, but CYP1A2, CYP3A6 and CYP2E1 are below limits of detection. RT-PCR was also used to compare mRNA levels of 11 different rabbit and six different rat P450 isoforms in the tongue to those in the liver of these two species. Only CYP2E1, CYP1A1 and CYP4A4 were detected at significant levels in the rabbit tongue. None of the six rat isoforms probed were observed in the tongue. Although 4-nitrophenol activity was observed in the rabbit tongue samples, the kinetic parameter Km was inconsistent with the involvement of CYP2E1. We suggest that although CYP2E1 is expressed in the tongue, it is rapidly degraded in this organ, and the nitrophenol hydroxylation and caffeine hydroxylation we observe is the result of activity of CYP1A1

Stopped-flow spectrophotometric analysis of intermediates in the peroxo-dependent inactivation of cytochrome P450 by aldehydes

The reaction of hydrogen peroxide and certain aromatic aldehydes with cytochrome P450BM3-F87G results in the covalent modification of the heme cofactor of this monooxygenase. Analysis of the resulting heme by electronic absorption spectrophotometry indicates that the reaction in the BM3 isoform is analogous to that in P4502B4, which apparently occurs via a peroxyhemiacetal intermediate [Kuo et al., Biochemistry, 38 (1999) 10511]. It was observed that replacement of the Phe-87 in the P450BM3 by the smaller glycyl residue was essential for the modification to proceed, as the wild-type enzyme showed no spectral changes under identical conditions. The kinetics of this reaction were examined by stopped-flow spectrophotometry with 3-phenylpropionaldehyde and 3-phenylbutyraldehyde as reactants. In each case, the process of heme modification was biphasic, with initial bleaching of the Soret absorbance, followed by an increase in absorbance centered at 430 nm, consistent with meso-heme adduct formation. The intermediate formed during phase I also showed an increased absorbance between 700 and 900 nm, relative to the native heme and the final product. Phase I showed a linear dependence on peroxide concentration, whereas saturation kinetics were observed for phase II. All of these observations are consistent with a mechanism involving radical attack at the &#x03B3-meso position of the heme cofactor, resulting in the intermediate formation of an isoporphyrin, the deprotonation of which produces the &#x03B3-meso-alkyl heme derivative

Farnesol as an inhibitor and substrate for rabbit liver microsomal P450 enzymes

Farnesol and the related isoprenoids, geranylgeraniol, geranylgeranyl pyrophosphate, and farnesyl pyrophosphate, are produced in the endoplasmic reticulum of hepatocytes in mammals, and each serve important biological functions. Of these compounds, only farnesol was shown to significantly inhibit rabbit liver microsomal cytochrome P450 enzymes. The observed inhibition appeared to be reversible, and was not strictly competitive, but rather mixed in nature. Of the activities examined, ethoxycoumarin de-ethylase and diclofenac-4-hydroxylase activities were most sensitive to farnesol, with KI and K’I values between 11 and 40 µM. Caffeine-8-hydroxylation and taxol-6-hydroxylation were not inhibited at all by farnesol. Farnesol appeared to be a P450 substrate, as well as an inhibitor, as indicated by the NADPH-dependent decrease in farnesol concentration in microsomal incubations, and the metabolism was inhibited by CO, which pointed to the involvement of P450 isozymes