CD4⁺ T-cell plasticity in non-infectious retinal inflammatory disease

Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4+ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4+FoxP3+CD25+ regulatory T cells (Tregs) were known to suppress function of effector CD4+ T cells and contribute to resolution of disease. It has been recently reported that some CD4+ T-cell subsets demonstrate shared phenotypes with another CD4+ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these ‘plastic CD4+ T cells’ are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease

Adhesion Molecule Targeted Therapy for Non-Infectious Uveitis

Non-infectious uveitis (NIU) is an inflammatory eye disease initiated via CD4+ T-cell activation and transmigration, resulting in focal retinal tissue damage and visual acuity disturbance. Cell adhesion molecules (CAMs) are activated during the inflammatory process to facilitate the leukocyte recruitment cascade. Our review focused on CAM-targeted therapies in experimental autoimmune uveitis (EAU) and NIU. We concluded that CAM-based therapies have demonstrated benefits for controlling EAU severity with decreases in immune cell migration, especially via ICAM-1/LFA-1 and VCAM-1/VLA-4 (integrin) pathways. P-selectin and E-selectin are more involved specifically in uveitis related to vasculitis. These therapies have potential clinical applications for the development of a more personalized and specific treatment. Localized therapies are the future direction to avoid serious systemic side effects

Leukotriene B4 (LTB4) and its receptor in Experimental Autoimmune Uveitis (EAU) and in human retinal tissues: clinical severity and LTB4-dependence of retinal Th17 cells

Nomacopan, a drug originally derived from tick saliva, has dual functions of sequestering leukotriene B4 (LTB4) and inhibiting complement component 5 (C5) activation. It was demonstrated that nomacopan provides therapeutic benefit in experimental autoimmune uveitis (EAU). The longer-acting forms of nomacopan were more efficacious in mouse EAU models and the long-acting variant that inhibited only LTB4 was at least as effective as the long-acting variant that inhibited both C5 and LTB4, preventing structural damage to the retina and a significant reduction of effector Th17 cells and inflammatory macrophages. Increased levels of LTB4 and C5a (produced upon C5 activation) were detected during disease progression. Retinal activated lymphocytes were shown to express LTB4 receptors (R) in vitro and in inflamed draining lymph nodes (dLN). Levels of LTB4R-expressing retinal active/inflammatory macrophages were also increased. Within the dLN CD4+T cell population, 30% expressed LTB4R+ following activation in vitro, while retinal infiltrating cells expressed LTB4R and C5aR. Validation of expression of those receptors in human uveitis and healthy tissues suggests that infiltrating cells could be targeted by inhibitors of the LTB4-BLT1 pathway as a novel therapeutic approach. In conclusion, this study provides novel data on intraocular LTB4 and C5a in EAU, their associated receptor expression by retinal infiltrating cells in mouse and human tissues and in attenuating EAU via the dual inhibitor nomacopan

Finite-Size Scaling Study of the Surface and Bulk Critical Behavior in the Random-Bond 8-state Potts Model

The self-dual random-bond eight-state Potts model is studied numerically through large-scale Monte Carlo simulations using the Swendsen-Wang cluster flipping algorithm. We compute bulk and surface order parameters and susceptibilities and deduce the corresponding critical exponents at the random fixed point using standard finite-size scaling techniques. The scaling laws are suitably satisfied. We find that a belonging of the model to the 2D Ising model universality class can be conclusively ruled out, and the dimensions of the relevant bulk and surface scaling fields are found to take the values $y_h=1.849$, $y_t=0.977$, $y_{h_s}=0.54$, to be compared to their Ising values: 15/8, 1, and 1/2.Comment: LaTeX file with Revtex, 4 pages, 4 eps figures, to appear in Phys. Rev. Let

Weak Randomness for large q-State Potts models in Two Dimensions

We have studied the effect of weak randomness on q-state Potts models for q > 4 by measuring the central charges of these models using transfer matrix methods. We obtain a set of new values for the central charges and then show that some of these values are related to one another by a factorization law.Comment: 8 pages, Latex, no figure

Comb-like pseudopeptides enable very rapid and efficient intracellular trehalose delivery for enhanced cryopreservation of erythrocytes

Cell cryopreservation plays a key role in development of reproducible and cost-effective cell-based therapies. Trehalose accumulated in freezing and desiccation tolerant organisms in nature has been sought as an attractive non-toxic cryoprotectant. Herein, we report a co-incubation method for very rapid and efficient delivery of membrane-impermeable trehalose into ovine erythrocytes through reversible membrane permeabilization using pH-responsive, comb-like pseudopeptides. The pseudopeptidic polymers containing relatively long alkyl side chains were synthesized to mimic membrane-anchoring fusogenic proteins. The intracellular trehalose delivery efficiency was optimized by manipulating the side chain length, degree of substitution and concentration of the pseudopeptides with different hydrophobic alkyl side chains, the pH, temperature and time of incubation, as well as the polymer-to-cell ratio and the concentration of extracellular trehalose. Treatment of erythrocytes with the comb-like pseudopeptides for only 15 min yielded an intracellular trehalose concentration of 177.9 ± 8.6 mM, which resulted in 90.3 ± 0.7% survival after freeze-thaw. The very rapid and efficient delivery was found to be attributed to the reversible, pronounced membrane curvature change as a result of strong membrane insertion of the comb-like pseudopeptides. The pseudopeptides can enable efficient intracellular delivery of not only trehalose for improved cell cryopreservation, but also other membrane-impermeable cargos

The Random-bond Potts model in the large-q limit

We study the critical behavior of the q-state Potts model with random ferromagnetic couplings. Working with the cluster representation the partition sum of the model in the large-q limit is dominated by a single graph, the fractal properties of which are related to the critical singularities of the random Potts model. The optimization problem of finding the dominant graph, is studied on the square lattice by simulated annealing and by a combinatorial algorithm. Critical exponents of the magnetization and the correlation length are estimated and conformal predictions are compared with numerical results.Comment: 7 pages, 6 figure

Evidence for softening of first-order transition in 3D by quenched disorder

We study by extensive Monte Carlo simulations the effect of random bond dilution on the phase transition of the three-dimensional 4-state Potts model which is known to exhibit a strong first-order transition in the pure case. The phase diagram in the dilution-temperature plane is determined from the peaks of the susceptibility for sufficiently large system sizes. In the strongly disordered regime, numerical evidence for softening to a second-order transition induced by randomness is given. Here a large-scale finite-size scaling analysis, made difficult due to strong crossover effects presumably caused by the percolation fixed point, is performed.Comment: LaTeX file with Revtex, 4 pages, 4 eps figure

Infrared generation in low-dimensional semiconductor heterostructures via quantum coherence

A new scheme for infrared generation without population inversion between subbands in quantum-well and quantum-dot lasers is presented and documented by detailed calculations. The scheme is based on the simultaneous generation at three frequencies: optical lasing at the two interband transitions which take place simultaneously, in the same active region, and serve as the coherent drive for the IR field. This mechanism for frequency down-conversion does not rely upon any ad hoc assumptions of long-lived coherences in the semiconductor active medium. And it should work efficiently at room temperature with injection current pumping. For optimized waveguide and cavity parameters, the intrinsic efficiency of the down-conversion process can reach the limiting quantum value corresponding to one infrared photon per one optical photon. Due to the parametric nature of IR generation, the proposed inversionless scheme is especially promising for long-wavelength (far- infrared) operation.Comment: 4 pages, 1 Postscript figure, Revtex style. Replacement corrects a printing error in the authors fiel

Recent changes of water discharge and sediment load in the Yellow River basin, China

The Yellow River basin contributes approximately 6% of the sediment load from all river systems globally, and the annual runoff directly supports 12% of the Chinese population. As a result, describing and understanding recent variations of water discharge and sediment load under global change scenarios are of considerable importance. The present study considers the annual hydrologic series of the water discharge and sediment load of the Yellow River basin obtained from 15 gauging stations (10 mainstream, 5 tributaries). The Mann-Kendall test method was adopted to detect both gradual and abrupt change of hydrological series since the 1950s. With the exception of the area draining to the Upper Tangnaihai station, results indicate that both water discharge and sediment load have decreased significantly (p<0.05). The declining trend is greater with distance downstream, and drainage area has a significant positive effect on the rate of decline. It is suggested that the abrupt change of the water discharge from the late 1980s to the early 1990s arose from human extraction, and that the abrupt change in sediment load was linked to disturbance from reservoir construction.Geography, PhysicalGeosciences, MultidisciplinarySCI(E)43ARTICLE4541-5613