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- Sawcer, Stephen, et al.
(author)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Journal article (peer-reviewed)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 3. |
- Gout, Thomas L., et al.
(author)
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Diffusive processes in aqueous glass dissolution
- 2019
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In: npj Materials Degradation. - : Springer Science and Business Media LLC. - 2397-2106. ; 3:1
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Journal article (peer-reviewed)abstract
- High level nuclear waste is often immobilised in a borosilicate glass for disposal. However, this glass corrodes in contact with aqueous solutions. To predict radionuclide releases from wasteforms, their dissolution mechanisms must be understood. Understanding glass dissolution mechanisms presents a challenge across numerous other disciplines and many glass dissolution models still remain conflicted. Here we show that diffusion was a significant process during the later stages of dissolution of a simplified waste glass but was not evidenced during the initial stages of dissolution. The absence of measurable isotopic fractionation in solution initially supports models of congruent dissolution. However, the solution becoming isotopically lighter at later times evidences diffusive isotopic fractionation and opposes models that exclude diffusive transport as a significant mechanism. The periodically sampled isotopic methodologies outlined here provide an additional dimension with which to understand glass dissolution mechanisms beyond the usual measurement of solution concentrations and, post-process, nano-scale analysis of the altered glass.
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| 4. |
- Gout, Thomas L., et al.
(author)
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Temperature dependent lithium isotope fractionation during glass dissolution
- 2021
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In: Geochimica et Cosmochimica Acta. - : Elsevier. - 0016-7037 .- 1872-9533. ; 313, s. 133-154
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Journal article (peer-reviewed)abstract
- Understanding the mechanisms by which borosilicate glasses corrode in contact with aqueous solutions remains a challenge to the safety case for the geological disposal of vitrified high-level nuclear waste. Here, lithium isotope fingerprinting techniques were applied to the leachates of a simulant Magnox waste glass to probe the mechanisms of aqueous corrosion at both short and long timescales (6 hours to 464 days). Experiments took place at 40 and 90 degrees C to assess the consistency of the dissolution mechanisms across a range of commonly employed temperatures and the legitimacy of applying higher temperature experimental datasets to understand glass corrosion within a disposal facility at lower temperatures. Two competing release mechanisms were observed for lithium (diffusion and hydrolysis), and the relative proportions of these mechanisms changed through time. Leachates initially had lower delta(7) Li values than the pristine glass (-2.7 parts per thousand at 40 degrees C and 1.1 parts per thousand at 90 degrees C relative to the pristine glass) at both temperatures due to lithium leaching incongruently through diffusive processes. The greater offset between solution and solid at lower temperatures indicates a larger rate of diffusion (incongruent dissolution) relative to the rate of hydrolysis (congruent dissolution) at lower temperatures. The fraction of lithium released through diffusion relative to the fraction of lithium released through hydrolysis then increased at both temperatures with time up to 126 days, increasing from 0.47 and 0.22 at 6 hours to 0.66 and 0.41 at 126 days at 40 and 90 degrees C respectively. Subsequently, the fractions of lithium released through diffusion sharply decreased to 0.36 at 40 degrees C and 0.22 at 90 degrees C after 464 days, consistent with network hydrolysis coupled with secondary phase precipitation later controlling the long-term release of Li at both temperatures. Throughout the duration of the experiments (464 days) the delta(7) Li values in solution increased to 9.0 parts per thousand at 40 degrees C and 10.0 parts per thousand at 90 degrees C due to the formation of talc and montmorillonite phases at 40 degrees C and additional smectite phases at 90 degrees C. Further, no evidence for the formation of a diffusive barrier to the transport of Li within the alteration layers became apparent during the later stages of dissolution at either temperature. However, the fraction of lithium leached through diffusion was still significant throughout all stages of dissolution. Lithium isotope ratios in solution were correlated with the transition from a system which was increasingly dominated by lithium diffusion as the dissolution rate slowed to one which was controlled by hydrolysis coupled with secondary phase precipitation at long durations. Alongside elemental ratios in solution, these results were consistent with the same set of mechanisms governing dissolution across the temperature range studied.
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