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- Gallagher, Michael D., et al.
(författare)
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TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions
- 2014
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Ingår i: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 127:3, s. 407-418
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Tidskriftsartikel (refereegranskat)abstract
- Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.
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| 2. |
- Way, Danielle A., et al.
(författare)
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Increasing water use efficiency along the C-3 to C-4 evolutionary pathway : a stomatal optimization perspective
- 2014
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Ingår i: Journal of Experimental Botany. - : Oxford University Press (OUP). - 0022-0957 .- 1460-2431. ; 65:13, s. 3683-3693
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Tidskriftsartikel (refereegranskat)abstract
- C-4 photosynthesis evolved independently numerous times, probably in response to declining atmospheric CO2 concentrations, but also to high temperatures and aridity, which enhance water losses through transpiration. Here, the environmental factors controlling stomatal behaviour of leaf-level carbon and water exchange were examined across the evolutionary continuum from C-3 to C-4 photosynthesis at current (400 mu mol mol(-1)) and low (280 mu mol mol(-1)) atmospheric CO2 conditions. To this aim, a stomatal optimization model was further developed to describe the evolutionary continuum from C-3 to C-4 species within a unified framework. Data on C-3, three categories of C-3-C-4 intermediates, and C-4 Flaveria species were used to parameterize the stomatal model, including parameters for the marginal water use efficiency and the efficiency of the CO2-concentrating mechanism (or C-4 pump); these two parameters are interpreted as traits reflecting the stomatal and photosynthetic adjustments during the C-3 to C-4 transformation. Neither the marginal water use efficiency nor the C-4 pump strength changed significantly from C-3 to early C-3-C-4 intermediate stages, but both traits significantly increased between early C-3-C-4 intermediates and the C-4-like intermediates with an operational C-4 cycle. At low CO2, net photosynthetic rates showed continuous increases from a C-3 state, across the intermediates and towards C-4 photosynthesis, but only C-4-like intermediates and C-4 species (with an operational C-4 cycle) had higher water use efficiencies than C-3 Flaveria. The results demonstrate that both the marginal water use efficiency and the C-4 pump strength increase in C-4 Flaveria to improve their photosynthesis and water use efficiency compared with C-3 species. These findings emphasize that the advantage of the early intermediate stages is predominantly carbon based, not water related.
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