Recipient iNOS but Not eNOS Deficiency Reduces Luminal Narrowing in Tracheal Allografts

Chronic airway rejection is characterized by prolonged inflammation, epithelial damage, and eventual luminal obliterative bronchiolitis (OB). In cardiac allografts, the inducible nitric oxide synthase (iNOS) promotes acute rejection but paradoxically reduces neointimal formation, the hallmark of chronic rejection. The specific roles of NOS isoforms in modulating lymphocyte traffic and airway rejection are not known. Using a double lumen mouse tracheal transplant model, tracheal grafts from B10.A (allo) or C57BL/6J (iso) mice were transplanted into cyclosporine-treated wild-type (WT) iNOS−/− or endothelial NOS (eNOS)−/− recipients. OB was observed in WT tracheal allografts at 3 weeks (53 ± 2% luminal occlusion vs. 17 ± 1% for isografts, P < 0.05) with sites of obstructive lesion formation coinciding with areas of CD3+ CD8+ T cell–rich lymphocytic bronchitis. In contrast, allografts in iNOS−/− recipients exhibited reductions in local expression of proinflammatory chemokines and cytokines, graft T cell recruitment and apoptosis, and luminal obliteration (29 ± 2%, P < 0.05 vs. WT allografts). Recipient eNOS deficiency, however, suppressed neither chemokine expression, lymphocyte infiltration, nor airway occlusion (54 ± 2%). These data demonstrate that iNOS exacerbates luminal obliteration of airway allografts in contrast with the known suppression by iNOS of cardiac allograft vasculopathy. Because iNOS−/− airways transplanted into WT allograft hosts are not protected from rejection, these data suggest that iNOS expressed by graft-infiltrating leukocytes exerts the dominant influence on airway rejection

The Model Cities Program

The period from 1961 through 1965 saw a dramatic increase in the number of federal grant-in-aid programs and the total federal funding levels directed at curing the ills of the urban community. There was a persistent anxiety, however, that, despite the proliferation of new drugs administered to the patient for his array of symptoms, the progress was not satisfactory, and that time was running out. In October, 1965, a Task Force on Urban Problems was appointed by President Johnson to study urban problems and recommend action. The Task Force looked at the prior efforts and decided a new approach was necessary-a treatment to be commenced in selected cities as a demonstration. They recommended that the federal, state and local medicine men consult with each other in order to develop a program of drug therapy which would be comprehensive, and coordinated. They also recommended that massive new types and higher dosage levels of drugs were necessary if the patient was to be revitalized. The basic Task Force recommendation was accepted by the President and presented to the Congress in his message of January 26, 1966. A proposed Demonstration Cities Act of 1966 was introduced into Congress, which was later consolidated with other provisions into an omnibus bill, and finally was enacted as Title I of the Demonstration Cities and Metropolitan Development Act of 1966. As HUD commenced to implement the new program, it was given its popular name, the Model Cities Program, a designation not appearing in the Act. This article presents this, program in its historical perspective and its posture as developed administratively by the Johnson Administration. Its full potential and direction will unfold during the Nixon Administration. Secretary of Housing and Urban Development, George W. Romney, has endorsed the concept underlying the Program and announced Presidential approval of certain revisions in the administration of the Program.\u2

Light-Front QCD(1+1) Coupled to Chiral Adjoint Fermions

We consider SU(N) gauge theory in 1+1 dimensions coupled to chiral fermions in the adjoint representation of the gauge group. With all fields in the adjoint representation the gauge group is actually SU(N)/Z_N, which possesses nontrivial topology. In particular, there are N distinct topological sectors and the physical vacuum state has a structure analogous to a \theta vacuum. We show how this feature is realized in light-front quantization for the case N=2, using discretization as an infrared regulator. In the discretized form of the theory the nontrivial vacuum structure is associated with the zero momentum mode of the gauge field A^+. We find exact expressions for the degenerate vacuum states and the analog of the \theta vacuum. The model also possess a condensate which we calculate. We discuss the difference between this chiral light-front theory and the theories that have previously been considered in the equal-time approach.Comment: 14 pages, RevTeX, two figures requiring BoxedEPS.tex. References added and some typos correcte

Molecular regulation of the PAI‐1 gene by hypoxia: contributions of Egr‐1, HIF‐1 α, and C/EBPα

Hypoxia, as occurs during tissue ischemia, tips the natural anticoagulant/procoagulant balance of the endovascular wall to favor activation of coagulation. Plasminogen activator inhibitor‐1 (PAI‐1) is an important factor suppressing fibrinolysis under conditions of low oxygen tension. We previously reported that hypoxia induced PAI‐1 mRNA and antigen expression in murine macrophages secondary to increased de novo transcription as well as increased mRNA stability. We now show in RAW264.7 murine macrophages that the transcription factors early growth response gene‐1 (Egr‐1), hypoxia‐inducible factor‐1α (HIF‐1α), and CCAAT/enhancer binding protein α (C/EBPα) are quickly activated in hypoxia and are responsible for transcription and expression of PAI‐1. Murine PAI‐1 promoter constructs, including Egr, HIF‐1α, and/or C/EBPα binding sites, were transfected into RAW 264.7 murine macrophages. To identify the relative importance of each of these putative hypoxia‐responsive elements, cells were exposed to normobaric hypoxia, and transcriptional activity was recorded. At 16 h of hypoxic exposure, murine PAI‐1 promoter deletion constructs that included Egr, HIF‐1α, and/or C/EBPα binding sites demonstrated increased tran‐scriptional activity. Mutation of each of these three murine PAI‐1 promoter sites (or a combination of them) resulted in a marked reduction in hypoxia sensitivity as detected by transcriptional analysis. Functional data obtained using 32P‐labeled Egr, HIF‐1 α response element (HRE), and C/EBPα oligonucleotides revealed induction of DNA binding activity in nuclear extracts from hypoxic RAW cells, with supershift analysis confirming activation of Egr‐1, HIF‐1 α, or C/EBPα. ChIP analysis confirmed the authenticity of these interactions as each of these transcription factors binds to chromatin under hypoxic conditions. Further, the induction of PAI‐1 by Egr‐1, HIF‐1 α, or C/EBPα was replicated in primary peritoneal macrophages. These data suggest that although HIF‐1 α appears to dominate the PAI‐1 transcriptional response in hyp‐oxia, Egr‐1 and C/EBPα greatly augment this response and can do so independent of HIF‐1α or each other. These studies are relevant to ischemic up‐regulation of the PAI‐1 gene and consequent accrual of micro‐vascular thrombus under ischemic conditions.—Liao, H., Hyman, M. C., Lawrence, D. A., Pinsky, D. J. Molecular regulation of the PAI‐1 gene by hypoxia: contributions of Egr‐1, HIF‐1α, and C/EBPα. FASEB J. 21, 935–949 (2007)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154298/1/fsb2fj066285com.pd

Regulation of ecto‐apyrase CD39 (ENTPD1) expression by phosphodiesterase III (PDE3)

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154432/1/fsb2027011011.pd

Vacuum Structure of Two-Dimensional Gauge Theories on the Light Front

We discuss the problem of vacuum structure in light-front field theory in the context of (1+1)-dimensional gauge theories. We begin by reviewing the known light-front solution of the Schwinger model, highlighting the issues that are relevant for reproducing the $\theta$-structure of the vacuum. The most important of these are the need to introduce degrees of freedom initialized on two different null planes, the proper incorporation of gauge field zero modes when periodicity conditions are used to regulate the infrared, and the importance of carefully regulating singular operator products in a gauge-invariant way. We then consider SU(2) Yang-Mills theory in 1+1 dimensions coupled to massless adjoint fermions. With all fields in the adjoint representation the gauge group is actually SU(2)$/Z_2$, which possesses nontrivial topology. In particular, there are two topological sectors and the physical vacuum state has a structure analogous to a $\theta$ vacuum. We formulate the model using periodicity conditions in $x^\pm$ for infrared regulation, and consider a solution in which the gauge field zero mode is treated as a constrained operator. We obtain the expected $Z_2$ vacuum structure, and verify that the discrete vacuum angle which enters has no effect on the spectrum of the theory. We then calculate the chiral condensate, which is sensitive to the vacuum structure. The result is nonzero, but inversely proportional to the periodicity length, a situation which is familiar from the Schwinger model. The origin of this behavior is discussed.Comment: 29 pages, uses RevTeX. Improved discussion of the physical subspace generally and the vacuum states in particular. Basic conclusions are unchanged, but some specific results are modifie

Analytic perturbation solution to the capacitance system of a hyberboloidal tip and a rough surface

The capacitance system of a hyperboloidal tip and a rough surface is usually encountered in analyzing electrostatic force microscopy images. In this letter, a perturbation approach has been applied to solve for the electric potential of this system, in which the rough surface is treated as perturbation from a flat one. For the first-variation solution, the boundary value problem is represented in the prolate-spheroidal coordinate system and solved in terms of a generalized Fourier series involving conical functions. Based on this solution, the tip-surface Coulombic interaction can be computed. Sample calculations have been applied to sinusoidal surface profilesPeer ReviewedPostprint (published version