79 research outputs found
Nitrated α–Synuclein Immunity Accelerates Degeneration of Nigral Dopaminergic Neurons
The neuropathology of Parkinson's disease (PD) includes loss of dopaminergic neurons in the substantia nigra, nitrated alpha-synuclein (N-alpha-Syn) enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration.Nitrotyrosine (NT)-modified alpha-Syn was detected readily in cervical lymph nodes (CLN) from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice. Antigen-presenting cells within the CLN showed increased surface expression of major histocompatibility complex class II, initiating the molecular machinery necessary for efficient antigen presentation. MPTP-treated mice produced antibodies to native and nitrated alpha-Syn. Mice immunized with the NT-modified C-terminal tail fragment of alpha-Syn, but not native protein, generated robust T cell proliferative and pro-inflammatory secretory responses specific only for the modified antigen. T cells generated against the nitrated epitope do not respond to the unmodified protein. Mice deficient in T and B lymphocytes were resistant to MPTP-induced neurodegeneration. Transfer of T cells from mice immunized with N-alpha-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss.These data show that NT modifications within alpha-Syn, can bypass or break immunological tolerance and activate peripheral leukocytes in draining lymphoid tissue. A novel mechanism for disease is made in that NT modifications in alpha-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and treatment of this disabling neurodegenerative disease
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The Tunnel Sealing Experiment: An In Situ Demonstration of Technologies for Vault Sealing
Two bulkheads, one composed of high performance concrete and the other of highly compacted sand-bentonite material, have been constructed in a tunnel in unfractured granite rock at the Underground Research Laboratory. The Tunnel Sealing Experiment will characterize the performance of the two bulkheads under applied hydraulic pressures. The chamber between the two bulkheads will be pressurized to approximately 4 MPa, a value representative of the ambient pore pressures in the rock at a depth of 420 m. Instrumentation in the experiment monitors the seepage through and around each bulkhead as well as the changes tot he pure water pressure, and hence changes to the flow directions,in the intact rock. Stresses and displacements in each bulkhead are also monitored. The objective of the experiment is to demonstrate technologies for contrustion of bentonite and concrete bulkheads and to quantify the performance of each bulkhead
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A shaft seal system for the Waste Isolation Pilot Plant
As part of the demonstration of compliance with federal regulations, a shaft seal system has been designed for the Waste Isolation Pilot Plant. The system completely fills the 650 m shafts with components consisting of the common engineering materials, each of which possesses low permeability, longevity, and can be constructed using available technology. Design investigations couple rock mechanics and fluid flow analysis and tests of these materials within the natural geological setting, and demonstrate the effectiveness of the design
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