Increased expression of cystine/glutamate antiporter in multiple sclerosis

Background: Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Intriguingly, glutamate level in plasma and cerebrospinal fluid of MS patients is elevated, a feature which may be related to the pathophysiology of this disease. In addition to glutamate transporters, levels of extracellular glutamate are controlled by cystine/glutamate antiporter x(c)(-), an exchanger that provides intracellular cystine for production of glutathione, the major cellular antioxidant. The objective of this study was to analyze the role of the system x(c)(-) in glutamate homeostasis alterations in MS pathology. -- Methods: Primary cultures of human monocytes and the cell line U-937 were used to investigate the mechanism of glutamate release. Expression of cystine glutamate exchanger (xCT) was quantified by quantitative PCR, Western blot, flow cytometry and immunohistochemistry in monocytes in vitro, in animals with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, and in samples of MS patients. -- Results and discussion: We show here that human activated monocytes release glutamate through cystine/glutamate antiporter x(c)(-) and that the expression of the catalytic subunit xCT is upregulated as a consequence of monocyte activation. In addition, xCT expression is also increased in EAE and in the disease proper. In the later, high expression of xCT occurs both in the central nervous system (CNS) and in peripheral blood cells. In particular, cells from monocyte-macrophage-microglia lineage have higher xCT expression in MS and in EAE, indicating that immune activation upregulates xCT levels, which may result in higher glutamate release and contribution to excitotoxic damage to oligodendrocytes. -- Conclusions: Together, these results reveal that increased expression of the cystine/glutamate antiporter system x(c)(-) in MS provides a link between inflammation and excitotoxicity in demyelinating diseases.

Oceanographic results from the ONR cruise 1, Lateral Transport Study, 3-7 June 1985

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Diffusive waves in a channel with concentrated lateral inflow

In the current paper an analytical solution for diffusive wave equation with the concentrate-distributed lateral inflow is yielded. Finite-difference numerical method is also employed to validate this model. The backwater effects drawn from lateral inflow on the mainstream are examined finally.

Simulating the Lateral Transport of lchthyoplankton in the Potomac Estuary

Previous simulations of potential ichthyoplankton entrainment by power generating stations on the Potomac estuary have not included the influence of lateral transport in distributing eggs and larvae over the nursery area. Therefore, two-dimensional, vertically-averaged hydrodynamic and kinematic models of passive organism transport were developed to represent advective and dispersive processes near the proposed Douglas Point Nuclear Generating Station. Although the more refined model did not substantially alter the estimate of ichthyoplankton entrainment, it did reveal that lateral inhomogeneities in hydrodynamics could engender several fold differences in entrainment probabilities on opposite sides of the estuary. Models of higher resolution and greater biological detail did not project greater total entrainment by the Douglas Point plant, because the volume of nontidal flow past the site was large in comparison to the proposed rate of cooling water withdrawal.

Lateral motion and departure of vapor bubbles in nucleate pool boiling on thin wires in microgravity

A space experiment on bubble behavior and heat transfer in subcooled pool boiling phenomenon has been performed utilizing the temperature-controlled pool boiling (TCPB) device both in normal gravity in the laboratory and in microgravity aboard the 22(nd) Chinese recoverable satellite. The fluid is R113 at 0.1 MPa and subcooled by 26 degrees C nominally. A thin platinum wire of 60 mu m in diameter and 30mm in length is simultaneously used as heater and thermometer. Only the lateral motion and the departure of discrete vapor bubbles in nucleate pool boiling are reported and analyzed in the present paper. A scale analysis on the Marangoni convection surrounding a bubble in the process of subcooled nucleate pool boiling leads to formulas of the characteristic velocity of the lateral motion and its observability. The predictions consist with the experimental observations. Considering the Marangoni effect, a new qualitative model is proposed to reveal the mechanism underlying the bubble departure processes and a quantitative agreement can also be acquired.

Fine mapping and functional analysis of the multiple sclerosis risk gene CD6

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2nd SRCR domain with susceptibility to MS (Pmax(T) permutation=161024). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. – CD4+ naı¨ve cells, P = 0.0001; CD8+ naı¨ve cells, P,0.0001; CD4+ and CD8+ central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4+ and CD8+ T cells.