Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x(c)- or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration. Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x(c)-, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT(-/-)) mice and irradiated mice reconstituted in xCT(-/-) bone marrow (BM), to their proper wild type (xCT(+/+)) controls. Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT(+/+) mice, xCT(-/-) mice were equally susceptible to EAE, whereas mice transplanted with xCT(-/-) BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected. Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS

Plate-boundary deformation associated with the great Sumatra–Andaman earthquake

The Sumatra–Andaman earthquake of 26 December 2004 is the first giant earthquake (moment magnitude M_w > 9.0) to have occurred since the advent of modern space-based geodesy and broadband seismology. It therefore provides an unprecedented opportunity to investigate the characteristics of one of these enormous and rare events. Here we report estimates of the ground displacement associated with this event, using near-field Global Positioning System (GPS) surveys in northwestern Sumatra combined with in situ and remote observations of the vertical motion of coral reefs. These data show that the earthquake was generated by rupture of the Sunda subduction megathrust over a distance of >1,500 kilometres and a width of <150 kilometres. Megathrust slip exceeded 20 metres offshore northern Sumatra, mostly at depths shallower than 30 kilometres. Comparison of the geodetically and seismically inferred slip distribution indicates that ~30 per cent additional fault slip accrued in the 1.5 months following the 500-second-long seismic rupture. Both seismic and aseismic slip before our re-occupation of GPS sites occurred on the shallow portion of the megathrust, where the large Aceh tsunami originated. Slip tapers off abruptly along strike beneath Simeulue Island at the southeastern edge of the rupture, where the earthquake nucleated and where an M_w = 7.2 earthquake occurred in late 2002. This edge also abuts the northern limit of slip in the 28 March 2005 M_w = 8.7 Nias–Simeulue earthquake