Using pH abnormalities in diseased skin to trigger and target topical therapy

Abstract Purpose: The pH discrepancy between healthy and atopic dermatitis skin was identified as a site specific trigger for delivering hydrocortisone from microcapsules. Methods: Using Eudragit L100, a pH-responsive polymer which dissolves at pH 6, hydrocortisone-loaded microparticles were produced by oil-in-oil microencapsulation or spray drying. Release and permeation of hydrocortisone from microparticles alone or in gels was assessed and preliminary stability data was determined. Results: Drug release from microparticles was pH-dependent though the particles produced by spray drying also gave significant non-pH dependent burst release, resulting from their porous nature or from drug enrichment on the surface of these particles. This pH-responsive release was maintained upon incorporation of the oil-in-oil microparticles into Carbopol- and HPMC-based gel formulations. In-vitro studies showed 4 to 5-fold higher drug permeation through porcine skin from the gels at pH 7 compared to pH 5. Conclusions: Permeation studies showed that the oil-in-oil generated particles deliver essentially no drug at normal (intact) skin pH (5.0 – 5.5) but that delivery can be triggered and targeted to atopic dermatitis skin where the pH is elevated. The incorporation of these microparticles into Carbopol- and HPMC-based aqueous gel formulations demonstrated good stability and pH-responsive permeation into porcine skin

Epithelial and extracellular matrix injury in quartz-inflamed lung: role of the alveolar macrophage.

The bronchoalveolar leukocytes from quartz-inflamed lung were separated into macrophage-enriched and neutrophil-enriched populations on density gradients. Neutrophil-enriched populations showed the greatest activity in causing injury to epithelial cells and fibronectin in vitro. Inflammatory macrophage-enriched populations from quartz-exposed lung had the ability to cause fibronectin degradation but could not cause detachment injury to epithelial cells over and above that caused by control alveolar macrophages. Fibronectin damage in vivo could be an important factor in disordering the connective tissue scaffold of the lung, thereby favoring fibrosis. In vitro quartz stimulated more production of cytokines by alveolar macrophages than the inert particulate titanium dioxide. Cytokines could be important in upregulating adhesion molecules in the membranes of lung cells in vivo; this process could aid leukocyte/lung cell contact, allowing epithelial injury to be expressed, and could also be a factor leading to pathological change

Numerical solution to the hermitian Yang-Mills equation on the Fermat quintic

We develop an iterative method for finding solutions to the hermitian Yang-Mills equation on stable holomorphic vector bundles, following ideas recently developed by Donaldson. As illustrations, we construct numerically the hermitian Einstein metrics on the tangent bundle and a rank three vector bundle on P^2. In addition, we find a hermitian Yang-Mills connection on a stable rank three vector bundle on the Fermat quintic.Comment: 25 pages, 2 figure

Simple matrix models for random Bergman metrics

Recently, the authors have proposed a new approach to the theory of random metrics, making an explicit link between probability measures on the space of metrics on a Kahler manifold and random matrix models. We consider simple examples of such models and compute the one and two-point functions of the metric. These geometric correlation functions correspond to new interesting types of matrix model correlators. We study a large class of examples and provide in particular a detailed study of the Wishart model.Comment: 23 pages, IOP Latex style, diastatic function Eq. (22) and contact terms in Eqs. (76, 95) corrected, typos fixed. Accepted to JSTA

Remarks on the naturality of quantization

Hamiltonian quantization of an integral compact symplectic manifold M depends on a choice of compatible almost complex structure J. For open sets U in the set of compatible almost complex structures and small enough values of Planck's constant, the Hilbert spaces of the quantization form a bundle over U with a natural connection. In this paper we examine the dependence of the Hilbert spaces on the choice of J, by computing the semi-classical limit of the curvature of this connection. We also show that parallel transport provides a link between the action of the group Symp(M) of symplectomorphisms of M and the Schrodinger equation.Comment: 20 page

On the spectrum of the Page and the Chen-LeBrun-Weber metrics

We give bounds on the first non-zero eigenvalue of the scalar Laplacian for both the Page and the Chen-LeBrun-Weber Einstein metrics. One notable feature is that these bounds are obtained without explicit knowledge of the metrics or numerical approximation to them. Our method also allows the calculation of the invariant part of the spectrum for both metrics. We go on to discuss an application of these bounds to the linear stability of the metrics. We also give numerical evidence to suggest that the bounds for both metrics are extremely close to the actual eigenvalue.Comment: 15 pages, v2 substantially rewritten, section on linear stability added; v3 updated to reflect referee's comments, v4 final version to appear in Ann. Glob. Anal. Geo

A practical laboratory method to determine ceftazidime-avibactam-aztreonam synergy in patients with New Delhi Metallo-beta-lactamase (NDM) producing Enterobacterales infection

Background: In response to infection with New Delhi Metallo-beta-lactamase (NDM) producing Enterobacterales, combination antimicrobial therapy with ceftazidime/avibactam (CAZ/AVI) plus aztreonam (ATM) has been explored. This study evaluated a practical laboratory method of testing for clinically significant synergy between CAZ/AVI+ATM in NDM producing Enterobacterales. Methods: Minimum inhibitory concentration (MIC) of clinical NDM producing isolates were determined for ATM alone and CAZ/AVI+ATM using broth dilution. Restoration of ATM breakpoint following the addition of CAZ/AVI was explored. A CAZ/AVI E-test/ATM disc method was compared to broth dilution. Results: Of 43 isolates, 33/43 (77%) isolates were ATM resistant (median [range] MIC=56 [16 – 512] mg/L). Addition of CAZ/AVI restored the ATM breakpoint (MIC <4mg/L) in 29/33 (89%) of resistant isolates. Overall, the E-test/disc method correlated with findings from broth dilution in 35/43 (81%) of cases. E-test/disc sensitivity was 77% and specificity 85%. Positive predictive value was 92% and negative predictive value 61%. Conclusion: CAZ/AVI+ATM demonstrated significant synergy in most ATM resistant NDM producing Enterobacterales. The E-test/disc method is a quick, reproducible, and reliable method of testing for clinically relevant synergy in the microbiology laboratory

Solutions of the Strominger System via Stable Bundles on Calabi-Yau Threefolds

We prove that a given Calabi-Yau threefold with a stable holomorphic vector bundle can be perturbed to a solution of the Strominger system provided that the second Chern class of the vector bundle is equal to the second Chern class of the tangent bundle. If the Calabi-Yau threefold has strict SU(3) holonomy then the equations of motion derived from the heterotic string effective action are also satisfied by the solutions we obtain.Comment: 19 pages, late

Sheaves on fibered threefolds and quiver sheaves

This paper classifies a class of holomorphic D-branes, closely related to framed torsion-free sheaves, on threefolds fibered in resolved ADE surfaces over a general curve C, in terms of representations with relations of a twisted Kronheimer--Nakajima-type quiver in the category Coh(C) of coherent sheaves on C. For the local Calabi--Yau case C\cong\A^1 and special choice of framing, one recovers the N=1 ADE quiver studied by Cachazo--Katz--Vafa.Comment: 13 pages, 2 figures, minor change

YAP/TAZ-CDC42 signaling regulates vascular tip cell migration

Angiogenesis and vascular remodeling are essential for the establishment of vascular networks during organogenesis. Here we show that the Hippo signaling pathway effectors YAP and TAZ are required, in a gene dosage-dependent manner, for the proliferation and migration of vascular endothelial cells (ECs) during retinal angiogenesis. Intriguingly, nuclear translocation of YAP and TAZ induced by Lats1/2-deletion blocked endothelial migration and phenocopied Yap/Taz-deficient mutants. Furthermore, overexpression of a cytoplasmic form of YAP (YAPS127D) partially rescued the migration defects caused by loss of YAP and TAZ function. Finally, we found that cytoplasmic YAP positively regulated the activity of the small GTPase CDC42, deletion of which caused severe defects in endothelial migration. These findings uncover a previously unrecognized role of cytoplasmic YAP/TAZ in promoting cell migration by activating CDC42 and provide insight into how Hippo signaling in ECs regulates angiogenesis