| 1. |
- Fenstermacher, M.E., et al.
(författare)
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DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
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Ingår i: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
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Tidskriftsartikel (refereegranskat)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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| 2. |
- Colbourne, JK, et al.
(författare)
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The Precision Toxicology initiative
- 2023
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Ingår i: Toxicology letters. - 1879-3169. ; 383, s. 33-42
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
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| 4. |
- Sterjovski, Jasminka, et al.
(författare)
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Asn 362 in gp120 contributes to enhanced fusogenicity by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with AIDS
- 2007
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Ingår i: Retrovirology. - : Springer Science and Business Media LLC. - 1742-4690. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: CCR5-restricted (R5) human immunodeficiency virus type 1 (HIV-1) variants cause CD4+ T-cell loss in the majority of individuals who progress to AIDS, but mechanisms underlying the pathogenicity of R5 strains are poorly understood. To better understand envelope glycoprotein (Env) determinants contributing to pathogenicity of R5 viruses, we characterized 37 full-length R5 Envs from cross-sectional and longitudinal R5 viruses isolated from blood of patients with asymptomatic infection or AIDS, referred to as pre-AIDS (PA) and AIDS (A) R5 Envs, respectively. Results: Compared to PA-R5 Envs, A-R5 Envs had enhanced fusogenicity in quantitative cell-cell fusion assays, and reduced sensitivity to inhibition by the fusion inhibitor T-20. Sequence analysis identified the presence of Asn 362 (N362), a potential N-linked glycosylation site immediately N-terminal to CD4-binding site (CD4bs) residues in the C3 region of gp120, more frequently in AR5 Envs than PA-R5 Envs. N362 was associated with enhanced fusogenicity, faster entry kinetics, and increased sensitivity of Env-pseudotyped reporter viruses to neutralization by the CD4bs-directed Env mAb IgG1b12. Mutagenesis studies showed N362 contributes to enhanced fusogenicity of most A-R5 Envs. Molecular models indicate N362 is located adjacent to the CD4 binding loop of gp120, and suggest N362 may enhance fusogenicity by promoting greater exposure of the CD4bs and/or stabilizing the CD4-bound Env structure. Conclusion: Enhanced fusogenicity is a phenotype of the A-R5 Envs studied, which was associated with the presence of N362, enhanced HIV-1 entry kinetics and increased CD4bs exposure in gp120. N362 contributes to fusogenicity of R5 Envs in a strain dependent manner. Our studies suggest enhanced fusogenicity of A-R5 Envs may contribute to CD4+ T-cell loss in subjects who progress to AIDS whilst harbouring R5 HIV-1 variants. N362 may contribute to this effect in some individuals.
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| 5. |
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| 6. |
- Wade, Jessica, et al.
(författare)
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Enhanced CD4+cellular apoptosis by CCR5-restricted HIV-1 envelope glycoprotein variants from patients with progressive HIV-1 infection
- 2010
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Ingår i: Virology. - : Elsevier BV. - 1096-0341 .- 0042-6822. ; 396:2, s. 246-255
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Tidskriftsartikel (refereegranskat)abstract
- CCR5-using (R5) human immunodeficiency virus type 1 (HIV-1) strains cause CD4+ T-cell loss in most infected individuals, but mechanisms underlying cytopathicity of R5 viruses are poorly understood. We investigated mechanisms contributing to R5 envelope glycoprotein (Env)-mediated cellular apoptosis by constructing a panel of retroviral vectors engineered to co-express GFP and R5 Envs derived from two HIV-1 infected subjects spanning asymptomatic (Early, E-R5 Envs) to late stages of infection (Late, L-R5 Envs). The L-R5 Envs induced significantly more cellular apoptosis than E-R5 Envs, but only in Env-expressing (GFP-positive) cells, and only in cells where CD4 and CCR5 levels were limiting. Studies with fusion-defective Env mutants showed induction of apoptosis required membrane-fusing events. Our results provide evidence for an intracellular mechanism of R5 Env-induced apoptosis of CD4+ cells that requires membrane fusion. Furthermore, they contribute to a better understanding of mechanisms involved in CD4+ T-cell loss in subjects experiencing progressive R5 HIV-1 infection. (C) 2009 Elsevier Inc. All rights reserved.
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| 7. |
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| 8. |
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| 9. |
- Borggren, Marie, et al.
(författare)
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Evolution of DC-SIGN use revealed by fitness studies of R5 HIV-I variants emerging during AIDS progression
- 2008
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Ingår i: Retrovirology. - : Springer Science and Business Media LLC. - 1742-4690. ; 5:28
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Tidskriftsartikel (refereegranskat)abstract
- Background: At early stages of infection CCR5 is the predominant HIV-1 coreceptor, but in approximately 50% of those infected CXCR4-using viruses emerge with disease progression. This coreceptor switch is correlated with an accelerated progression. However, those that maintain virus exclusively restricted to CCR5 (R5) also develop AIDS. We have previously reported that R5 variants in these "non-switch virus" patients evolve during disease progression towards a more replicative phenotype exhibiting altered CCR5 coreceptor interactions. DC-SIGN is a C-type lectin expressed by dendritic cells that HIV-1 may bind and utilize for enhanced infection of T cells in trans. To further explore the evolution of the R5 phenotype we analyzed sequential R5 isolates obtained before and after AIDS onset, i.e. at the chronic stage and during end-stage disease, with regard to efficiency of DC-SIGN use in trans-infections. Results: Results from binding and trans-infection assays showed that R5 viruses emerging during end-stage AIDS disease displayed reduced ability to use DC-SIGN. To better understand viral determinants underlying altered DC-SIGN usage by R5 viruses, we cloned and sequenced the HIV-1 env gene. We found that end-stage R5 viruses lacked potential N-linked glycosylation sites (PNGS) in the gp120 V2 and V4 regions, which were present in the majority of the chronic stage R5 variants. One of these sites, amino acid position 160 (aa160) in the V2 region, also correlated with efficient use of DC-SIGN for binding and trans-infections. In fitness assays, where head-to-head competitions between chronic stage and AIDS R5 viruses were setup in parallel direct and DCSIGN-mediated infections, results were further supported. Competitions revealed that R5 viruses obtained before AIDS onset, containing the V2 PNGS at aa160, were selected for in the transinfection. Whereas, in agreement with our previous studies, the opposite was seen in direct target cell infections where end-stage viruses out-competed the chronic stage viruses. Conclusion: Results of our study suggest R5 virus variants with diverse fitness for direct and DCSIGN-mediated trans-infections evolve within infected individuals at end-stage disease. In addition, our results point to the importance of a glycosylation site within the gp120 V2 region for efficient DC-SIGN use of HIV-1 R5 viruses.
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| 10. |
- Borggren, Marie, et al.
(författare)
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Increased Sensitivity to Broadly Neutralizing Antibodies of End-Stage Disease R5 HIV-1 Correlates with Evolution in Env Glycosylation and Charge.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Induction of broadly neutralizing antibodies, such as the monoclonal antibodies IgGb12, 2F5 and 2G12, is the objective of most antibody-based HIV-1 vaccine undertakings. However, despite the relative conserved nature of epitopes targeted by these antibodies, mechanisms underlying the sensitivity of circulating HIV-1 variants to broadly neutralizing antibodies are not fully understood. Here we have studied sensitivity to broadly neutralizing antibodies of HIV-1 variants that emerge during disease progression in relation to molecular alterations in the viral envelope glycoproteins (Env), using a panel of primary R5 HIV-1 isolates sequentially obtained before and after AIDS onset.
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| 11. |
- Didion, JP, et al.
(författare)
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R2d2 Drives Selfish Sweeps in the House Mouse
- 2016
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 1537-1719 .- 0737-4038. ; 33:6, s. 1381-1395
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Tidskriftsartikel (refereegranskat)
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| 12. |
- Gorgolewski, Krzysztof J., et al.
(författare)
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BIDS apps: Improving ease of use, accessibility, and reproducibility of neuroimaging data analysis methods
- 2017
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Ingår i: PloS Computational Biology. - : Public Library of Science (PLoS). - 1553-734X .- 1553-7358. ; 13:3
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Tidskriftsartikel (refereegranskat)abstract
- The rate of progress in human neurosciences is limited by the inability to easily apply a wide range of analysis methods to the plethora of different datasets acquired in labs around the world. In this work, we introduce a framework for creating, testing, versioning and archiving portable applications for analyzing neuroimaging data organized and described in compliance with the Brain Imaging Data Structure (BIDS). The portability of these applications (BIDS Apps) is achieved by using container technologies that encapsulate all binary and other dependencies in one convenient package. BIDS Apps run on all three major operating systems with no need for complex setup and configuration and thanks to the comprehensiveness of the BIDS standard they require little manual user input. Previous containerized data processing solutions were limited to single user environments and not compatible with most multi-tenant High Performance Computing systems. BIDS Apps overcome this limitation by taking advantage of the Singularity container technology. As a proof of concept, this work is accompanied by 22 ready to use BIDS Apps, packaging a diverse set of commonly used neuroimaging algorithms.
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| 13. |
- Hartstone-Rose, Adam, et al.
(författare)
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The Plio-Pleistocene ancestor of wild dogs, Lycaon sekowei n. sp.
- 2010
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Ingår i: Journal of Paleontology. - 0022-3360 .- 1937-2337. ; 84, s. 299-308
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Tidskriftsartikel (refereegranskat)abstract
- African wild dogs (Lycaon pictus) occupy an ecological niche characterized by hypercarnivory and cursorial hunting. Previous interpretations drawn from a limited, mostly Eurasian fossil record suggest that the evolutionary shift to cursorial hunting preceded the emergence of hypercarnivory in the Lycaon lineage. Here we describe 1.9–1.0 ma fossils from two South African sites representing a putative ancestor of the wild dog. The holotype is a nearly complete maxilla from Coopers Cave, and another specimen tentatively assigned to the new taxon, from Gladysvale, is the most nearly complete mammalian skeleton ever described from the Sterkfontein Valley, Gauteng, South Africa. The canid represented by these fossils is larger and more robust than are any of the other fossil or extant sub-Saharan canids. Unlike other purported L. pictus ancestors, it has distinct accessory cusps on its premolars and anterior accessory cuspids on its lower premolars–a trait unique to Lycaon among living canids. However, another hallmark autapomorphy of L. pictus, the tetradactyl manus, is not found in the new species; the Gladysvale skeleton includes a large first metacarpal. Thus, the anatomy of this new early member of the Lycaon branch suggests that, contrary to previous hypotheses, dietary specialization appears to have preceded cursorial hunting in the evolution of the Lycaon lineage. We assign these specimens to the taxon Lycaon sekowei n. sp.
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| 14. |
- He, Guiying, et al.
(författare)
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Promoting multiexciton interactions in singlet fission and triplet fusion upconversion dendrimers
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Singlet fission and triplet-triplet annihilation upconversion are two multiexciton processes intimately related to the dynamic interaction between one high-lying energy singlet and two low-lying energy triplet excitons. Here, we introduce a series of dendritic macromolecules that serve as platform to study the effect of interchromophore interactions on the dynamics of multiexciton generation and decay as a function of dendrimer generation. The dendrimers (generations 1–4) consist of trimethylolpropane core and 2,2-bis(methylol)propionic acid (bis-MPA) dendrons that provide exponential growth of the branches, leading to a corona decorated with pentacenes for SF or anthracenes for TTA-UC. The findings reveal a trend where a few highly ordered sites emerge as the dendrimer generation grows, dominating the multiexciton dynamics, as deduced from optical spectra, and transient absorption spectroscopy. While the dendritic structures enhance TTA-UC at low annihilator concentrations in the largest dendrimers, the paired chromophore interactions induce a broadened and red-shifted excimer emission. In SF dendrimers of higher generations, the triplet dynamics become increasingly dominated by pairwise sites exhibiting strong coupling (Type II), which can be readily distinguished from sites with weaker coupling (Type I) by their spectral dynamics and decay kinetics.
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| 15. |
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| 16. |
- Repits, Johanna, et al.
(författare)
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Primary HIV-1 R5 isolates from end-stage disease display enhanced viral fitness in parallel with increased gp120 net charge.
- 2008
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Ingår i: Virology. - : Elsevier BV. - 1096-0341 .- 0042-6822. ; 379:1, s. 125-134
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Tidskriftsartikel (refereegranskat)abstract
- To better understand the evolution of the viral envelope glycoproteins (Env) in HIV-1 infected individuals who progress to AIDS maintaining an exclusive CCR5-using (R5) virus population, we cloned and sequenced the env gene of longitudinally obtained primary isolates. A shift in the electrostatic potential towards an increased net positive charge was revealed in gp120 of end-stage viruses. Residues with increased positive charge were primarily localized in the gp120 variable regions, with the exception of the V3 loop. Molecular modeling indicated that the modifications clustered on the gp120 surface. Furthermore, correlations between increased Env net charge and lowered CD4(+) T cell counts, enhanced viral fitness, reduced sensitivity to entry inhibitors and augmented cell attachment were disclosed. In summary, this study suggests that R5 HIV-1 variants with increased gp120 net charge emerge in an opportunistic manner during severe immunodeficiency. Thus, we here propose a new mechanism by which HIV-1 may gain fitness.
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