IL-10 production in macrophages is regulated by a TLR-driven CREB-mediated mechanism that is linked to genes involved in cell metabolism

IL-10 is produced by macrophages in diverse immune settings and is critical in limiting immune-mediated pathology. In helminth infections, macrophages are an important source of IL-10; however, the molecular mechanism underpinning production of IL-10 by these cells is poorly characterized. In this study, bone marrow–derived macrophages exposed to excretory/secretory products released by Schistosoma mansoni cercariae rapidly produce IL-10 as a result of MyD88-mediated activation of MEK/ERK/RSK and p38. The phosphorylation of these kinases was triggered by TLR2 and TLR4 and converged on activation of the transcription factor CREB. Following phosphorylation, CREB is recruited to a novel regulatory element in the Il10 promoter and is also responsible for regulating a network of genes involved in metabolic processes, such as glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Moreover, skin-resident tissue macrophages, which encounter S. mansoni excretory/secretory products during infection, are the first monocytes to produce IL-10 in vivo early postinfection with S. mansoni cercariae. The early and rapid release of IL-10 by these cells has the potential to condition the dermal microenvironment encountered by immune cells recruited to this infection site, and we propose a mechanism by which CREB regulates the production of IL-10 by macrophages in the skin, but also has a major effect on their metabolic state

CD4+ T cell hyporesponsiveness after repeated exposure to Schistosoma mansoni larvae is dependent upon interleukin-10

The effect that multiple percutaneous exposures to Schistosoma larvae has on the development of early CD4+ lymphocyte reactivity is unclear, yet it is important in the context of humans living in areas where schistosomiasis is endemic. In a murine model of multiple infections, we show that exposure of mice to repeated doses (4×) of Schistosoma mansoni cercariae, compared to a single dose (1×), results in CD4+ T cell hyporesponsiveness within the skin-draining lymph nodes (sdLN), manifested as reduced CD4+ cell proliferation and cytokine production. FoxP3+ CD4+ regulatory T cells were present in similar numbers in the sdLN of 4× and 1× mice and thus are unlikely to have a role in effecting hyporesponsiveness. Moreover, anergy of the CD4+ cell population from 4× mice was slight, as proliferation was only partly circumvented through the in vitro addition of exogenous interleukin-2 (IL-2), and the in vivo blockade of the regulatory molecule PD1 had a minimal effect on restoring responsiveness. In contrast, IL-10 was observed to be critical in mediating hyporesponsiveness, as CD4+ cells from the sdLN of 4× mice deficient for IL-10 were readily able to proliferate, unlike those from 4× wild-type cohorts. CD4+ cells from the sdLN of 4× mice exhibited higher levels of apoptosis and cell death, but in the absence of IL-10, there was significantly less cell death. Combined, our data show that IL-10 is a key factor in the development of CD4+ T cell hyporesponsiveness after repeated parasite exposure involving CD4+ cell apoptosis

Spectral properties of a partially spin-polarized one-dimensional Hubbard/Luttinger superfluid

We calculate the excitation spectra of a spin-polarized Hubbard chain away from half-filling, using a high-precision momentum-resolved time-dependent Density Matrix Renormalization Group method. Focusing on the U<0 case, we present in some detail the single-fermion, pair, density and spin spectra, and discuss how spin-charge separation is altered for this system. The pair spectra show a quasi-condensate at a nonzero momentum proportional to the polarization, as expected for this Fulde-Ferrel-Larkin-Ovchinnikov-like superfluid.Comment: 4 pages, 3 low resolution color fig

MRI-derived arterial input functions for PET kinetic modelling in rats

Simultaneous PET–MR acquisition provides the high temporal and spatial resolution of MRI with the specificity of PET. In PET, accurate modelling of physiological function in vivo requires the time-activity curve of tracer in blood plasma, known as the arterial input function (AIF). As the gold standard method of blood sampling is inherently prohibitive in the small animal case, here we discuss how we prepare to rapidly sample MRI signals from gadolinium-doped tracer to obtain the tracer input functions from a simultaneous PET-MR measurement. ΔR2⁎ measurements taken from EPI images were used to obtain first pass bolus AIFs in the rat brain from DSC-MRI datasets of 5 rats. AIFs obtained using our automatic algorithm were found to be consistent between animals and compared well with manual methods without need for a priori voxel selection. A variable flip angle FLASH sequence used for T1 mapping was successfully tested in a phantom study, providing accurate measurements of Gd concentration.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org10.1016/j.nima.2012.08.08

Spectral properties of a spin-incoherent Luttinger Liquid

We present time-dependent density matrix renormalization group (DMRG) results for strongly interacting one dimensional fermionic systems at finite temperature. When interactions are strong the characteristic spin energy can be greatly suppressed relative to the characteristic charge energy, allowing for the possibility of spin-incoherent Luttinger liquid physics when the temperature is high compared to the spin energy, but small compared to the charge energy. Using DMRG we compute the spectral properties of the $t-J$ model at arbitrary temperatures with respect to both spin and charge energies. We study the full crossover from the Luttinger liquid regime to the spin-incoherent regime,focusing on small $J/t$, where the signatures of spin-incoherent behavior are more manifest. Our method allows us to access the analytically intractable regime where temperature is of the order of the spin energy, $T\sim J$. Our results should be helpful in the interpretation of experiments that may be in the crossover regime, $T\sim J$, and apply to one-dimensional cold atomic gases where finite-temperature effects are appreciable. The technique may also be used to guide the development of analytical approximations for the crossover regime.Comment: 7 pages, 5 figure

Finite Temperature Density Matrix Renormalization using an enlarged Hilbert space

We apply a generalization of the time-dependent DMRG to study finite temperature properties of several quantum spin chains, including the frustrated $J_1-J_2$ model. We discuss several practical issues with the method, including use of quantum numbers and finite size effects. We compare with transfer-matrix DMRG, finding that both methods produce excellent results.Comment: 4 pages and 4 figure

On the Hierarchical Preconditioning of the PMCHWT Integral Equation on Simply and Multiply Connected Geometries

We present a hierarchical basis preconditioning strategy for the Poggio-Miller-Chang-Harrington-Wu-Tsai (PMCHWT) integral equation considering both simply and multiply connected geometries.To this end, we first consider the direct application of hierarchical basis preconditioners, developed for the Electric Field Integral Equation (EFIE), to the PMCHWT. It is notably found that, whereas for the EFIE a diagonal preconditioner can be used for obtaining the hierarchical basis scaling factors, this strategy is catastrophic in the case of the PMCHWT since it leads to a severly ill-conditioned PMCHWT system in the case of multiply connected geometries. We then proceed to a theoretical analysis of the effect of hierarchical bases on the PMCHWT operator for which we obtain the correct scaling factors and a provably effective preconditioner for both low frequencies and mesh refinements. Numerical results will corroborate the theory and show the effectiveness of our approach

Numerical optimization of integrating cavities for diffraction-limited millimeter-wave bolometer arrays

Far-infrared to millimeter-wave bolometers designed to make astronomical observations are typically encased in integrating cavities at the termination of feedhorns or Winston cones. This photometer combination maximizes absorption of radiation, enables the absorber area to be minimized, and controls the directivity of absorption, thereby reducing susceptibility to stray light. In the next decade, arrays of hundreds of silicon nitride micromesh bolometers with planar architectures will be used in ground-based, suborbital, and orbital platforms for astronomy. The optimization of integrating cavity designs is required for achieving the highest possible sensitivity for these arrays. We report numerical simulations of the electromagnetic fields in integrating cavities with an infinite plane-parallel geometry formed by a solid reflecting backshort and the back surface of a feedhorn array block. Performance of this architecture for the bolometer array camera (Bolocam) for cosmology at a frequency of 214 GHz is investigated. We explore the sensitivity of absorption efficiency to absorber impedance and backshort location and the magnitude of leakage from cavities. The simulations are compared with experimental data from a room-temperature scale model and with the performance of Bolocam at a temperature of 300 mK. The main results of the simulations for Bolocam-type cavities are that (1) monochromatic absorptions as high as 95% are achievable with <1% cross talk between neighboring cavities, (2) the optimum absorber impedances are 400 Ω/sq, but with a broad maximum from ~150 to ~700 Ω/sq, and (3) maximum absorption is achieved with absorber diameters ≥1.5λ. Good general agreement between the simulations and the experiments was found

Junctions of multiple quantum wires with different Luttinger parameters

Within the framework of boundary conformal field theory, we evaluate the conductance of stable fixed points of junctions of two and three quantum wires with different Luttinger parameters. For two wires, the physical properties are governed by a single effective Luttinger parameters for each of the charge and spin sectors. We present numerical density-matrix-renormalization-group calculations of the conductance of a junction of two chains of interacting spinless fermions with different interaction strengths, obtained using a recently developed method [Phys. Rev. Lett. 105, 226803 (2010)]. The numerical results show very good agreement with the analytical predictions. For three spinless wires, i.e., a Y junction, we analytically determine the full phase diagram, and compute all fixed-point conductances as a function of the three Luttinger parameters.Comment: 13 pages, 6 figure

Steered Molecular Dynamic Simulations Reveal Marfan Syndrome Mutations Disrupt Fibrillin-1 cbEGF Domain Mechanosensitive Balcium Binding

Marfan syndrome (MFS) is a highly variable genetic connective tissue disorder caused by mutations in the calcium binding extracellular matrix glycoprotein fibrillin-1. Patients with the most severe form of MFS (neonatal MFS; nMFS) tend to have mutations that cluster in an internal region of fibrillin-1 called the neonatal region. This region is predominantly composed of eight calcium-binding epidermal growth factor-like (cbEGF) domains, each of which binds one calcium ion and is stabilized by three highly conserved disulfide bonds. Crucially, calcium plays a fundamental role in stabilizing cbEGF domains. Perturbed calcium binding caused by cbEGF domain mutations is thus thought to be a central driver of MFS pathophysiology. Using steered molecular dynamics (SMD) simulations, we demonstrate that cbEGF domain calcium binding decreases under mechanical stress (i.e. cbEGF domains are mechanosensitive). We further demonstrate the disulfide bonds in cbEGF domains uniquely orchestrate protein unfolding by showing that MFS disulfide bond mutations markedly disrupt normal mechanosensitive calcium binding dynamics. These results point to a potential mechanosensitive mechanism for fibrillin-1 in regulating extracellular transforming growth factor beta (TGFB) bioavailability and microfibril integrity. Such mechanosensitive smart features may represent novel mechanisms for mechanical hemostasis regulation in extracellular matrix that are pathologically activated in MFS