Identification of Therapeutic Targets of Inflammatory Monocyte Recruitment to Modulate the Allogeneic Injury to Donor Cornea

Purpose: We sought to test the hypothesis that monocytes contribute to the immunopathogenesis of corneal allograft rejection and identify therapeutic targets to inhibit monocyte recruitment. Methods: Monocytes and proinflammatory mediators within anterior chamber samples during corneal graft rejection were quantified by flow cytometry and multiplex protein assays. Lipopolysaccharide or IFN-γ stimulation of monocyte-derived macrophages (MDMs) was used to generate inflammatory conditioned media (CoM). Corneal endothelial viability was tested by nuclear counting, connexin 43, and propidium iodide staining. Chemokine and chemokine receptor expression in monocytes and MDMs was assessed in microarray transcriptomic data. The role of chemokine pathways in monocyte migration across microvascular endothelium was tested in vitro by chemokine depletion or chemokine receptor inhibitors. Results: Inflammatory monocytes were significantly enriched in anterior chamber samples within 1 week of the onset of symptoms of corneal graft rejection. The MDM inflammatory CoM was cytopathic to transformed human corneal endothelia. This effect was also evident in endothelium of excised human cornea and increased in the presence of monocytes. Gene expression microarrays identified monocyte chemokine receptors and cognate chemokines in MDM inflammatory responses, which were also enriched in anterior chamber samples. Depletion of selected chemokines in MDM inflammatory CoM had no effect on monocyte transmigration across an endothelial blood–eye barrier, but selective chemokine receptor inhibition reduced monocyte recruitment significantly. Conclusions: We propose a role for inflammatory monocytes in endothelial cytotoxicity in corneal graft rejection. Therefore, targeting monocyte recruitment offers a putative novel strategy to reduce donor endothelial cell injury in survival of human corneal allografts

Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies

published_or_final_versio

D-Branes on the Conifold and N=1 Gauge/Gravity Dualities

We review extensions of the AdS/CFT correspondence to gauge/ gravity dualities with N=1 supersymmetry. In particular, we describe the gauge/gravity dualities that emerge from placing D3-branes at the apex of the conifold. We consider first the conformal case, with discussions of chiral primary operators and wrapped D-branes. Next, we break the conformal symmetry by adding a stack of partially wrapped D5-branes to the system, changing the gauge group and introducing a logarithmic renormalization group flow. In the gravity dual, the effect of these wrapped D5-branes is to turn on the flux of 3-form field strengths. The associated RR 2-form potential breaks the U(1) R-symmetry to $Z_{2M}$ and we study this phenomenon in detail. This extra flux also leads to deformation of the cone near the apex, which describes the chiral symmetry breaking and confinement in the dual gauge theory.Comment: Based on I.R.K.'s lectures at the Les Houches Summer School Session 76, ``Gravity, Gauge Theories, and Strings'', August 2001, 42 pages, v2: clarifications and references adde

ABJM Baryon Stability and Myers effect

We consider magnetically charged baryon vertex like configurations in AdS^4 X CP^3 with a reduced number of quarks l. We show that these configurations are solutions to the classical equations of motion and are stable beyond a critical value of l. Given that the magnetic flux dissolves D0-brane charge it is possible to give a microscopical description in terms of D0-branes expanding into fuzzy CP^n spaces by Myers dielectric effect. Using this description we are able to explore the region of finite 't Hooft coupling.Comment: 29 pages, Latex; minor changes; version to appear in JHE

Scalar and vector mesons of flavor chiral symmetry breaking in the Klebanov-Strassler background

Recently, Dymarsky, Kuperstein and Sonnenschein constructed an embedding of flavor D7- and anti-D7-branes in the Klebanov-Strassler geometry that breaks the supersymmetry of the background, yet is stable. In this article, we study in detail the spectrum of vector mesons in this new model of flavor chiral symmetry breaking and commence an analytical analysis of the scalar mesons in this setup.Comment: v1: 35 pages, 5 figures, 4 tables, includes self-contained review of DKS construction; v2: corrected signs in eqs. (2.22) and (2.23), improved discussion of scalar mesons in section 3.2; v3: major revision of the results on scalar mesons, version submitted to JHEP; v4: version accepted by JHE

Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis

Following Mycobacterium tuberculosis (Mtb) infection, immune cell recruitment in lungs is pivotal in establishing protective immunity through granuloma formation and neogenesis of lymphoid structures (LS). Interferon regulatory factor-8 (IRF-8) plays an important role in host defense against Mtb, although the mechanisms driving anti-mycobacterial immunity remain unclear. In this study, IRF-8 deficient mice (IRF-8−/−) were aerogenously infected with a low-dose Mtb Erdman virulent strain and the course of infection was compared with that induced in wild-type (WT-B6) counterparts. Tuberculosis (TB) progression was examined in both groups using pathological, microbiological and immunological parameters. Following Mtb exposure, the bacterial load in lungs and spleens progressed comparably in the two groups for two weeks, after which IRF-8−/− mice developed a fatal acute TB whereas in WT-B6 the disease reached a chronic stage. In lungs of IRF-8−/−, uncontrolled growth of pulmonary granulomas and impaired development of LS were observed, associated with unbalanced homeostatic chemokines, progressive loss of infiltrating T lymphocytes and massive prevalence of neutrophils at late infection stages. Our data define IRF-8 as an essential factor for the maintenance of proper immune cell recruitment in granulomas and LS required to restrain Mtb infection. Moreover, IRF-8−/− mice, relying on a common human and mouse genetic mutation linked to susceptibility/severity of mycobacterial diseases, represent a valuable model of acute TB for comparative studies with chronically-infected congenic WT-B6 for dissecting protective and pathological immune reactions

Numerical studies of the ABJM theory for arbitrary N at arbitrary coupling constant

We show that the ABJM theory, which is an N=6 superconformal U(N)*U(N) Chern-Simons gauge theory, can be studied for arbitrary N at arbitrary coupling constant by applying a simple Monte Carlo method to the matrix model that can be derived from the theory by using the localization technique. This opens up the possibility of probing the quantum aspects of M-theory and testing the AdS_4/CFT_3 duality at the quantum level. Here we calculate the free energy, and confirm the N^{3/2} scaling in the M-theory limit predicted from the gravity side. We also find that our results nicely interpolate the analytical formulae proposed previously in the M-theory and type IIA regimes. Furthermore, we show that some results obtained by the Fermi gas approach can be clearly understood from the constant map contribution obtained by the genus expansion. The method can be easily generalized to the calculations of BPS operators and to other theories that reduce to matrix models.Comment: 35 pages, 20 figures; reference added. The simulation code is available upon request to [email protected]

The formation of professional identity in medical students: considerations for educators

<b>Context</b> Medical education is about more than acquiring an appropriate level of knowledge and developing relevant skills. To practice medicine students need to develop a professional identity – ways of being and relating in professional contexts.<p></p> <b>Objectives</b> This article conceptualises the processes underlying the formation and maintenance of medical students’ professional identity drawing on concepts from social psychology.<p></p> <b>Implications</b> A multi-dimensional model of identity and identity formation, along with the concepts of identity capital and multiple identities, are presented. The implications for educators are discussed.<p></p> <b>Conclusions</b> Identity formation is mainly social and relational in nature. Educators, and the wider medical society, need to utilise and maximise the opportunities that exist in the various relational settings students experience. Education in its broadest sense is about the transformation of the self into new ways of thinking and relating. Helping students form, and successfully integrate their professional selves into their multiple identities, is a fundamental of medical education

Moduli Stabilization and Cosmology of Type IIB on SU(2)-Structure Orientifolds

We consider type IIB flux compactifications on six-dimensional SU(2)-structure manifolds with O5- and O7-planes. These six-dimensional spaces allow not only for F_3 and H_3 fluxes but also for F_1 and F_5 fluxes. We derive the four-dimensional N=1 scalar potential for such compactifications and present one explicit example of a fully stabilized AdS vacuum with large volume and small string coupling. We then discuss cosmological aspects of these compactifications and derive several no-go theorems that forbid dS vacua and slow-roll inflation under certain conditions. We also study concrete examples of cosets and twisted tori and find that our no-go theorems forbid dS vacua and slow-roll inflation in all but one of them. For the latter we find a dS critical point with \epsilon numerically zero. However, the point has two tachyons and eta-parameter \eta \approx -3.1.Comment: 35 pages + appendices, LaTeX2e; v2: numerical dS extremum added, typos corrected, references adde

Thermodynamics of deformed AdS5_5 model with a positive/negative quadratic correction in graviton-dilaton system

By solving the Einstein equations of the graviton coupling with a real scalar dilaton field, we establish a general framework to self-consistently solve the geometric background with black-hole for any given phenomenological holographic models. In this framwork, we solve the black-hole background, the corresponding dilaon field and the dilaton potential for the deformed AdS$_5$ model with a positive/negative quadratic correction. We systematically investigate the thermodynamical properties of the deformed AdS$_5$ model with a positive and negative quadratic correction, respectively, and compare with lattice QCD on the results of the equation of state, the heavy quark potential, the Polyakov loop and the spatial Wilson loop. We find that the bulk thermodynamical properties are not sensitive to the sign of the quadratic correction, and the results of both deformed holographic QCD models agree well with lattice QCD result for pure SU(3) gauge theory. However, the results from loop operators favor a positive quadratic correction, which agree well with lattice QCD result. Especially, the result from the Polyakov loop excludes the model with a negative quadratic correction in the warp factor of ${\rm AdS}_5$.Comment: 26 figures,36 pages,V.3: an appendix,more equations and references added,figures corrected,published versio