Local delivery of novel MRTF/SRF inhibitors prevents scar tissue formation in a preclinical model of fibrosis

The myocardin-related transcription factor/serum response factor (MRTF/SRF) pathway represents a promising therapeutic target to prevent fibrosis. We have tested the effects of new pharmacological inhibitors of MRTF/SRF signalling in a preclinical model of fibrosis. CCG-222740, a novel MRTF/SRF inhibitor, markedly decreased SRF reporter gene activity and showed a greater inhibitory effect on MRTF/SRF target genes than the previously described MRTF-A inhibitor CCG-203971. CCG-222740 was also five times more potent, with an IC50 of 5 μM, in a fibroblast-mediated collagen contraction assay, was less cytotoxic, and a more potent inhibitor of alpha-smooth muscle actin protein expression than CCG-203971. Local delivery of CCG-222740 and CCG-203971 in a validated and clinically relevant rabbit model of scar tissue formation after glaucoma filtration surgery increased the long-term success of the surgery by 67% (P < 0.0005) and 33% (P < 0.01), respectively, and significantly decreased fibrosis and scarring histologically. Unlike mitomycin-C, neither CCG-222740 nor CCG-203971 caused any detectable epithelial toxicity or systemic side effects with very low drug levels measured in the aqueous, vitreous, and serum. We conclude that inhibitors of MRTF/SRF-regulated gene transcription such as CCG-222740, potentially represent a new therapeutic strategy to prevent scar tissue formation in the eye and other tissues

Generalized scaling function from light-cone gauge AdS_5 x S^5 superstring

We revisit the computation of the 2-loop correction to the energy of a folded spinning string in AdS_5 with an angular momentum J in S^5 in the scaling limit log S, J >>1 with J / log S fixed. This correction gives the third term in the strong-coupling expansion of the generalized scaling function. The computation, using the AdS light-cone gauge approach developed in our previous paper, is done by expanding the AdS_5 x S^5 superstring partition function near the generalized null cusp world surface associated to the spinning string solution. The result corrects and extends the previous conformal gauge result of arXiv:0712.2479 and is found to be in complete agreement with the corresponding terms in the generalized scaling function as obtained from the asymptotic Bethe ansatz in arXiv:0805.4615 (and also partially from the quantum O(6) model and the Bethe ansatz data in arXiv:0809.4952). This provides a highly nontrivial strong coupling comparison of the Bethe ansatz proposal with the quantum AdS_5 x S^5 superstring theory, which goes beyond the leading semiclassical term effectively controlled by the underlying algebraic curve. The 2-loop computation we perform involves all the structures in the AdS light-cone gauge superstring action of hep-th/0009171 and thus tests its ultraviolet finiteness and, through the agreement with the Bethe ansatz, its quantum integrability. We do most of the computations for a generalized spinning string solution or the corresponding null cusp surface that involves both the orbital momentum and the winding in a large circle of S^5.Comment: 50 pages, late

New Penrose Limits and AdS/CFT

We find a new Penrose limit of AdS_5 x S^5 giving the maximally supersymmetric pp-wave background with two explicit space-like isometries. This is an important missing piece in studying the AdS/CFT correspondence in certain subsectors. In particular whereas the Penrose limit giving one space-like isometry is useful for the SU(2) sector of N=4 SYM, this new Penrose limit is instead useful for studying the SU(2|3) and SU(1,2|3) sectors. In addition to the new Penrose limit of AdS_5 x S^5 we also find a new Penrose limit of AdS_4 x CP^3.Comment: 30 page

Towards outperforming conventional sensor arrays with fabricated individual photonic vapour sensors inspired by Morpho butterflies.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, Non-P.H.S.Combining vapour sensors into arrays is an accepted compromise to mitigate poor selectivity of conventional sensors. Here we show individual nanofabricated sensors that not only selectively detect separate vapours in pristine conditions but also quantify these vapours in mixtures, and when blended with a variable moisture background. Our sensor design is inspired by the iridescent nanostructure and gradient surface chemistry of Morpho butterflies and involves physical and chemical design criteria. The physical design involves optical interference and diffraction on the fabricated periodic nanostructures and uses optical loss in the nanostructure to enhance the spectral diversity of reflectance. The chemical design uses spatially controlled nanostructure functionalization. Thus, while quantitation of analytes in the presence of variable backgrounds is challenging for most sensor arrays, we achieve this goal using individual multivariable sensors. These colorimetric sensors can be tuned for numerous vapour sensing scenarios in confined areas or as individual nodes for distributed monitoring.We would like to acknowledge H. Ghiradella (University at Albany), M. Blohm and S. Duclos (GE) and V. Greanya, J. Abo-Shaeer, C. Nehl and M. Sandrock (DARPA) for fruitful discussions. This work has been supported in part from DARPA contract W911NF-10-C-0069 ‘Bio Inspired Photonics’ and from General Electric’s Advanced Technology research funds. The content of the information does not necessarily reflect the position or the policy of the US Government

In vitro and in vivo delivery of a sustained release nanocarrier-based formulation of an MRTF/SRF inhibitor in conjunctival fibrosis

BACKGROUND: Sustained drug delivery is a large unmet clinical need in glaucoma. Here, we incorporated a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor, CCG-222740, into slow release large unilamellar vesicles derived from the liposomes DOTMA (1,2-di-O-octadecenyl-3-trimethylammonium propane) and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), and tested their effects in vitro and in vivo. RESULTS: The vesicles were spherical particles of around 130 nm and were strongly cationic. A large amount of inhibitor could be incorporated into the vesicles. We showed that the nanocarrier CCG-222740 formulation gradually released the inhibitor over 14 days using high performance liquid chromatography. Nanocarrier CCG-222740 significantly decreased ACTA2 gene expression and was not cytotoxic in human conjunctival fibroblasts. In vivo, nanocarrier CCG-222740 doubled the bleb survival from 11.0 ± 0.6 days to 22.0 ± 1.3 days (p = 0.001), decreased conjunctival scarring and did not have any local or systemic adverse effects in a rabbit model of glaucoma filtration surgery. CONCLUSIONS: Our study demonstrates proof-of-concept that a nanocarrier-based formulation efficiently achieves a sustained release of a Myocardin-Related Transcription Factor/Serum Response Factor inhibitor and prevents conjunctival fibrosis in an established rabbit model of glaucoma filtration surgery

Black holes and black strings of N=2, d=5 supergravity in the H-FGK formalism

We study general classes and properties of extremal and non-extremal static black-hole solutions of N=2, d=5 supergravity coupled to vector multiplets using the recently proposed H-FGK formalism, which we also extend to static black strings. We explain how to determine the integration constants and physical parameters of the black-hole and black-string solutions. We derive some model-independent statements, including the transformation of non-extremal flow equations to the form of those for the extremal flow. We apply our methods to the construction of example solutions (among others a new extremal string solution of heterotic string theory on K_3 \times S^1). In the cases where we have calculated it explicitly, the product of areas of the inner and outer horizon of a non-extremal solution coincides with the square of the moduli-independent area of the horizon of the extremal solution with the same charges.Comment: 33 pages. Revised version: references added. No other change

Duality covariant non-BPS first order systems

We study extremal black hole solutions to four dimensional N=2 supergravity based on a cubic symmetric scalar manifold. Using the coset construction available for these models, we define the first order flow equations implied by the corresponding nilpotency conditions on the three-dimensional scalar momenta for the composite non-BPS class of multi-centre black holes. As an application, we directly solve these equations for the single-centre subclass, and write the general solution in a manifestly duality covariant form. This includes all single-centre under-rotating non-BPS solutions, as well as their non-interacting multi-centre generalisations.Comment: 31 pages, v2: Discussion of the quadratic constraint clarified, references added, typos corrected, published versio

DNA Methylation of the ABO Promoter Underlies Loss of ABO Allelic Expression in a Significant Proportion of Leukemic Patients

Background: Loss of A, B and H antigens from the red blood cells of patients with myeloid malignancies is a frequent occurrence. Previously, we have reported alterations in ABH antigens on the red blood cells of 55% of patients with myeloid malignancies. Methodology/Principal Findings: To determine the underlying molecular mechanisms of this loss, we assessed ABO allelic expression in 21 patients with ABH antigen loss previously identified by flow cytometric analysis as well as an additional 7 patients detected with ABH antigen changes by serology. When assessing ABO mRNA allelic expression, 6/12 (50%) patients with ABH antigen loss detected by flow cytometry and 5/7 (71%) of the patients with ABH antigen loss detected by serology had a corresponding ABO mRNA allelic loss of expression. We examined the ABO locus for copy number and DNA methylation alterations in 21 patients, 11 with loss of expression of one or both ABO alleles, and 10 patients with no detectable allelic loss of ABO mRNA expression. No loss of heterozygosity (LOH) at the ABO locus was observed in these patients. However in 8/11 (73%) patients with loss of ABO allelic expression, the ABO promoter was methylated compared with 2/10 (20%) of patients with no ABO allelic expression loss (P = 0.03). Conclusions/Significance: We have found that loss of ABH antigens in patients with hematological malignancies is associated with a corresponding loss of ABO allelic expression in a significant proportion of patients. Loss of ABO allelic expression was strongly associated with DNA methylation of the ABO promoter.Tina Bianco-Miotto, Damian J. Hussey, Tanya K. Day, Denise S. O'Keefe and Alexander Dobrovi

Associations between Screen Time and Physical Activity among Spanish Adolescents

Excessive time in front of a single or several screens could explain a displacement of physical activity. The present study aimed at determining whether screen-time is associated with a reduced level of moderate to vigorous physical activity (MVPA) in Spanish adolescents living in favorable environmental conditions. or more to total screen-time showed a 64% (OR = 0.61, 95% CI, 0.44–0.86) increased risk of failing to achieve the recommended adolescent MVPA level. Participation in organized physical activities and sports competitions were more strongly associated with MVPA than screen-related behaviors.No single screen-related behavior explained the reduction of MVPA in adolescents. However, the total time accumulated through several screen-related behaviors was negatively associated with MVPA level in boys. This association could be due to lower availability of time for exercise as the time devoted to sedentary screen-time activities increases. Participation in organized physical activities seems to counteract the negative impact of excessive time in front of screens on physical activity

First-order flows and stabilisation equations for non-BPS extremal black holes

We derive a generalised form of flow equations for extremal static and rotating non-BPS black holes in four-dimensional ungauged N = 2 supergravity coupled to vector multiplets. For particular charge vectors, we give stabilisation equations for the scalars, analogous to the BPS case, describing full known solutions. Based on this, we propose a generic ansatz for the stabilisation equations, which surprisingly includes ratios of harmonic functions.Comment: 27 pages; v2: presentation improved and references added as in the published versio