Asparaginyl endopeptidase (Legumain) supports human Th1 induction via cathepsin L-mediated intracellular C3 activation

Autocrine activation of the complement receptors C3aR and CD46 by complement activation components C3a and C3b produced through C3 cleavage by the protease cathepsin L (CTSL) during T cell stimulation is a requirement for IFN-γ production and Th1 induction in human CD4+ T cells. Thus, lack of autocrine CD46 activation, such as in CD46-deficient patients, is associated with defective Th1 responses and recurrent infections. We have identified LGMN [the gene coding for legumain, also known as asparaginyl endopeptidase (AEP)] as one of the key genes induced by CD46 co-stimulation during human CD4+ T cell activation. AEP processes and activates a range of proteins, among those α1-thymosin and CTSL, which both drive intrinsically Th1 activity—but has so far not been described to be functionally active in human T cells. Here we found that pharmacological inhibition of AEP during activation of human CD4+ T cells reduced CTSL activation and the CTSL-mediated generation of intracellular C3a. This translated into a specific reduction of IFN-γ production without affecting cell proliferation or survival. In line with these findings, CD4+ T cells isolated from Lgmn−/− mice also displayed a specific defect in IFN-γ secretion and Th1 induction. Furthermore, we did not observe a role for AEP-driven autocrine α1-thymosin activation in T cell-derived IFN-γ production. These data suggest that AEP is an “upstream” activator of the CTSL-C3-IFN-γ axis in human CD4+ T cells and hence an important supporter of human Th1 induction

Adaptive Wavelet Collocation Method on the Shallow Water Model

This paper presents an integrated approach for modeling several ocean test problems on adaptive grids using novel boundary techniques. The adaptive wavelet collocation method solves the governing equations on temporally and spatially varying meshes, which allows higher effective resolution to be obtained with less computational cost. It is a general method for the solving a large class of partial differential equations, but is applied to the shallow water equations here. In addition to developing wavelet-based computational models, this work also uses an extension of the Brinkman penalization method to represent irregular and non-uniform continental boundaries. This technique is used to enforce no slip boundary conditions through the addition of a term to the field equations. When coupled with the adaptive wavelet collocation method, the flow near the boundary can be well resolved. It is especially useful for simulations of boundary currents and tsunamis, where flow and the boundary is important, thus, those are the test cases presented here

Adaptive volume penalization for ocean modeling

The development of various volume penalization techniques for use in modeling topographical features in the ocean is the focus of this paper. Due to the complicated geometry inherent in ocean boundaries, the stair-step representation used in the majority of current global ocean circulation models causes accuracy and numerical stability problems. Brinkman penalization is the basis for the methods developed here and is a numerical technique used to enforce no-slip boundary conditions through the addition of a term to the governing equations. The second aspect to this proposed approach is that all governing equations are solved on a nonuniform, adaptive grid through the use of the adaptive wavelet collocation method. This method solves the governing equations on temporally and spatially varying meshes, which allows higher effective resolution to be obtained with less computational cost. When penalization methods are coupled with the adaptive wavelet collocation method, the flow near the boundary can be well-resolved. It is especially useful for simulations of boundary currents and tsunamis, where flow near the boundary is important. This paper will give a thorough analysis of these methods applied to the shallow water equations, as well as some preliminary work applying these methods to volume penalization for bathymetry representation for use in either the nonhydrostatic or hydrostatic primitive equations

Genomic and non-genomic regulation of PGC1 isoforms by estrogen to increase cerebral vascular mitochondrial biogenesis and reactive oxygen species protection

We previously found that estrogen exerts a novel protective effect on mitochondria in brain vasculature. Here we demonstrate in rat cerebral blood vessels that 17beta-estradiol (estrogen), both in vivo and ex vivo, affects key transcriptional coactivators responsible for mitochondrial regulation. Treatment of ovariectomized rats with estrogen in vivo lowered mRNA levels of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1alpha) but increased levels of the other PGC-1 isoforms: PGC-1beta and PGC-1 related coactivator (PRC). In vessels ex vivo, estrogen decreased protein levels of PGC-1alpha via activation of phosphatidylinositol 3-kinase (PI3K). Estrogen treatment also increased phosphorylation of forkhead transcription factor, FoxO1, a known pathway for PGC-1alpha downregulation. In contrast to the decrease in PGC-1alpha, estrogen increased protein levels of nuclear respiratory factor 1, a known PGC target and mediator of mitochondrial biogenesis. The latter effect of estrogen was independent of PI3K, suggesting a separate mechanism consistent with increased expression of PGC-1beta and PRC. We demonstrated increased mitochondrial biogenesis following estrogen treatment in vivo; cerebrovascular levels of mitochondrial transcription factor A and electron transport chain subunits as well as the mitochondrial/nuclear DNA ratio were increased. We examined a downstream target of PGC-1beta, glutamate-cysteine ligase (GCL), the rate-limiting enzyme for glutathione synthesis. In vivo estrogen increased protein levels of both GCL subunits and total glutathione levels. Together these data show estrogen differentially regulates PGC-1 isoforms in brain vasculature, underscoring the importance of these coactivators in adapting mitochondria in specific tissues. By upregulating PGC-1beta and/or PRC, estrogen appears to enhance mitochondrial biogenesis, function and reactive oxygen species protection

Theoretical description of high-order harmonic generation in solids

We consider several aspects of high-order harmonic generation in solids: the effects of elastic and inelastic scattering; varying pulse characteristics; and inclusion of material-specific parameters through a realistic band structure. We reproduce many observed characteristics of high harmonic generation experiments in solids including the formation of only odd harmonics in inversion-symmetric materials, and the nonlinear formation of high harmonics with increasing field. We find that the harmonic spectra are fairly robust against elastic and inelastic scattering. Furthermore, we find that the pulse characteristics play an important role in determining the harmonic spectra.Comment: Accepted for publication in the New Journal of Physic