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- Stork, D., et al.
(författare)
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Overview of transport, fast particle and heating and current drive physics using tritium in JET plasmas
- 2005
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Ingår i: Nuclear Fusion. - 0029-5515 .- 1741-4326. ; 45:10, s. S181-S194
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Tidskriftsartikel (refereegranskat)abstract
- Results are presented from the JET Trace Tritium Experimental (TTE) campaign using minority tritium (T) plasmas (n(T)/n(D) < 3%). Thermal tritium particle transport coefficients (D-T, nu(T)) are found to exceed neo-classical values in all regimes, except in ELMy H-modes at high densities and in the region of internal transport barriers (ITBs) in reversed shear plasmas. In ELMy H-mode dimensionless parameter scans, at q(95) 2.8 and triangularity delta = 0.2, the T particle transport scales in a gyro-Bohm manner in the inner plasma (r/a < 0.4), whilst the outer plasma particle transport scaling is more Bohm-like. Dimensionless parameter scans show contrasting behaviour for the trace particle confinement (increases with collisionality, nu* and beta) and bulk energy confinement (decreases with nu* and is independent of beta). In an extended ELMy H-mode data set, with rho*, nu*, and q varied but with neo-classical tearing modes (NTMs) either absent or limited to weak, benign core modes (4/3 or above), the multiparameter fit to the normalized diffusion coefficient in the outer plasma (0.65 < r/a < 0.8) gives D-T/B-phi similar to rho*(2.46) nu*(-0.23) beta(-1.01) q(2.03). In hybrid scenarios (q(min) similar to 1, low positive shear, no sawteeth), the T particle confinement is found to scale with increasing triangularity and plasma current. Comparing regimes (ELMy H-mode, ITB plasma and hybrid scenarios) in the outer plasma region, a correlation of high values of D-T with high values Of nu(T) is seen. The normalized diffusion coefficients for the hybrid and ITB scenarios do not fit the scaling derived for ELMy H-modes. The normalized tritium diffusion scales with normalized poloidal Larmor radius (rho(theta)* = q rho*) in a manner close to gyro-Bohm (similar to rho(sigma)*(3)), with an added inverse P dependence. The effects of ELMs, sawteeth and NTMs on the T particle transport are described. Fast-ion confinement in current-hole (CH) plasmas was tested in TTE by tritium neutral beam injection into JET CH plasmas. gamma-rays from the reactions of fusion alpha and beryllium impurities (Be-9(alpha, n gamma)C-12) characterized the fast fusion-alpha population evolution. The gamma-decay times are consistent with classical alpha plus parent fast triton slowing down times (tau(Ts) + tau(alpha s)) for high plasma currents (I-p > 2 MA) and monotonic q-profiles. In CH discharges the gamma-ray emission decay times are much lower than classical (tau(Ts) + tau(alpha s)), indicating alpha confinement degradation, due to the orbit losses and particle orbit drift predicted by a 3-D Fokker-Planck numerical code and modelled using TRANSP.
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- Grosche, S, et al.
(författare)
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Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 6618-
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema.
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- Baptista, Marisa A. P., et al.
(författare)
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Deletion of Wiskott-Aldrich syndrome protein triggers Rac2 activity and increased cross-presentation by dendritic cells
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Wiskott-Aldrich syndrome (WAS) is caused by loss-of-function mutations in the WASp gene. Decreased cellular responses in WASp-deficient cells have been interpreted to mean that WASp directly regulates these responses in WASp-sufficient cells. Here, we identify an exception to this concept and show that WASp-deficient dendritic cells have increased activation of Rac2 that support cross-presentation to CD8(+) T cells. Using two different skin pathology models, WASp-deficient mice show an accumulation of dendritic cells in the skin and increased expansion of IFN gamma-producing CD8(+) T cells in the draining lymph node and spleen. Specific deletion of WASp in dendritic cells leads to marked expansion of CD8(+) T cells at the expense of CD4(+) T cells. WASp-deficient dendritic cells induce increased cross-presentation to CD8(+) T cells by activating Rac2 that maintains a near neutral pH of phagosomes. Our data reveals an intricate balance between activation of WASp and Rac2 signalling pathways in dendritic cells.
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- Blundell, MP, et al.
(författare)
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Phosphorylation of WASp is a key regulator of activity and stability in vivo
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 106:37, s. 15738-15743
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Tidskriftsartikel (refereegranskat)abstract
- The Wiskott-Aldrich syndrome protein (WASp) is a key cytoskeletal regulator in hematopoietic cells. Covalent modification of a conserved tyrosine by phosphorylation has emerged as an important potential determinant of activity, although the physiological significance remains uncertain. In a murine knockin model, mutation resulting in inability to phosphorylate Y293 (Y293F) mimicked many features of complete WASp-deficiency. Although a phosphomimicking mutant Y293E conferred enhanced actin-polymerization, the cellular phenotype was similar due to functional dysregulation. Furthermore, steady-state levels of Y293E-WASp were markedly reduced compared to wild-type WASp and Y293F-WASp, although partially recoverable by treatment of cells with proteasome inhibitors. Consequently, tyrosine phosphorylation plays a critical role in normal activation of WASp in vivo, and is indispensible for multiple tasks including proliferation, phagocytosis, chemotaxis, and assembly of adhesion structures. Furthermore, it may target WASp for proteasome-mediated degradation, thereby providing a default mechanism for self-limiting stimulation of the Arp2/3 complex.
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- Cardoni, Simone, et al.
(författare)
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5S‐IGS rDNA in wind‐pollinated trees ( Fagus L.) encapsulates 55 million years of reticulate evolution and hybrid origins of modern species
- 2021
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Ingår i: The Plant Journal. - : Wiley. - 0960-7412 .- 1365-313X. ; 109:4, s. 909-926
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Tidskriftsartikel (refereegranskat)abstract
- Standard models of plant speciation assume strictly dichotomous genealogies in which a species, theancestor, is replaced by two offspring species. The reality in wind-pollinated trees with long evolutionaryhistories is more complex: species evolve from other species through isolation when genetic drift exceeds gene flow; lineage mixing can give rise to new species (hybrid taxa such as nothospecies and allopolyploids). The multi-copy, potentially multi-locus 5S rDNA is one of few gene regions conserving signal from dichotomous and reticulate evolutionary processes down to the level of intra-genomic recombination. Therefore, it can provide unique insights into the dynamic speciation processes of lineages that diversified tens of millions of years ago. Here, we provide the first high-throughput sequencing (HTS) of the 5S intergenic spacers (5S-IGS) for a lineage of wind-pollinated subtropical to temperate trees, the Fagus crenata – F.sylvatica s.l. lineage, and its distant relative F. japonica. The observed 4963 unique 5S-IGS variants reflect acomplex history of hybrid origins, lineage sorting, mixing via secondary gene flow, and intra-genomic competition between two or more paralogous-homoeologous 5S rDNA lineages. We show that modern species are genetic mosaics and represent a striking case of ongoing reticulate evolution during the past 55 million years.
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- Lankester, Arjan C, et al.
(författare)
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Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort.
- 2022
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Ingår i: The Journal of allergy and clinical immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 149:5
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Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome.We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome.HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed.Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P<.001). The 2-year event-free survival (EFS) was similar in matched and mismatched unrelated donor and less favorable in mismatched related donor (MMRD) HSCT (P< .001). Genetic subgroups did not differ in 2-year OS (P= .1) and EFS (P=.073). In multivariate analysis, pretransplantation infections and use of MMRDs were associated with less favorable OS and EFS. With a median follow-up of 6.2 years (range, 2.0-11.8 years), 73 of 152 patients in the IR cohort were alive and well without Ig dependency. IL-2 receptor gamma chain/Janus kinase 3/IL-7 receptor-deficient SCID, myeloablative conditioning, matched donor HSCT, and naive CD4 T lymphocytes >0.5×10e3/μL at+1 year were identified as independent predictors of favorable clinical and immunologic outcome.Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.
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