Deciphering the impact of uncertainty on the accuracy of large wildfire spread simulations

Predicting wildfire spread is a challenging task fraught with uncertainties. ‘Perfect’ predictions are unfeasible since uncertainties will always be present. Improving fire spread predictions is important to reduce its negative environmental impacts. Here, we propose to understand, characterize, and quantify the impact of uncertainty in the accuracy of fire spread predictions for very large wildfires. We frame this work from the perspective of the major problems commonly faced by fire model users, namely the necessity of accounting for uncertainty in input data to produce reliable and useful fire spread predictions. Uncertainty in input variables was propagated throughout the modeling framework and its impact was evaluated by estimating the spatial discrepancy between simulated and satellite-observed fire progression data, for eight very large wildfires in Portugal. Results showed that uncertainties in wind speed and direction, fuel model assignment and typology, location and timing of ignitions, had a major impact on prediction accuracy.We argue that uncertainties in these variables should be integrated in future fire spread simulation approaches, and provide the necessary data for any firemodel user to do soinfo:eu-repo/semantics/publishedVersio

Dual-Affinity Re-Targeting proteins direct T cell-mediated cytolysis of latently HIV-infected cells

Enhancement of HIV-specific immunity is likely required to eliminate latent HIV infection. Here, we have developed an immunotherapeutic modality aimed to improve T cell-mediated clearance of HIV-1-infected cells. Specifically, we employed Dual-Affinity Re-Targeting (DART) proteins, which are bispecific, antibody-based molecules that can bind 2 distinct cell-surface molecules simultaneously. We designed DARTs with a monovalent HIV-1 envelope-binding (Env-binding) arm that was derived from broadly binding, antibody-dependent cellular cytotoxicity-mediating antibodies known to bind to HIV-infected target cells coupled to a monovalent CD3 binding arm designed to engage cytolytic effector T cells (referred to as HIVxCD3 DARTs). Thus, these DARTs redirected polyclonal T cells to specifically engage with and kill Env-expressing cells, including CD4+ T cells infected with different HIV-1 subtypes, thereby obviating the requirement for HIV-specific immunity. Using lymphocytes from patients on suppressive antiretroviral therapy (ART), we demonstrated that DARTs mediate CD8+ T cell clearance of CD4+ T cells that are superinfected with the HIV-1 strain JR-CSF or infected with autologous reservoir viruses isolated from HIV-infected-patient resting CD4+ T cells. Moreover, DARTs mediated CD8+ T cell clearance of HIV from resting CD4+ T cell cultures following induction of latent virus expression. Combined with HIV latency reversing agents, HIVxCD3 DARTs have the potential to be effective immunotherapeutic agents to clear latent HIV-1 reservoirs in HIV-infected individuals

Lipid-free fluoropolymer-based propofol emulsions and lipid reversal of propofol anesthesia in rats

Background: Propofol, as a lipid-based emulsion, is effective at inducing anesthesia. It does, however, suffer from several drawbacks, including microbial growth, hyperlipidemia, and pain on injection. In this study, the authors examined the ability of four lipid-free propofol nanoemulsions to induce anesthesia in rats and tested whether a subsequent lipid bolus would accelerate emergence from anesthesia. Methods: The authors administered five formulations of propofol intravenously to six rats, delivering five different doses five times each, in a repeated-measures randomized crossover design and measured time to loss and recovery of righting reflex. The formulations included (1) Diprivan (AstraZeneca, United Kingdom); (2) L3, incorporating a semifluorinated surfactant plus egg lecithin; (3) B8, incorporating a semifluorinated surfactant only; (4) F8, incorporating a semifluorinated surfactant plus perfluorooctyl bromide; and (5) L80, incorporating egg lecithin only. In a second phase of the study, the authors administered a lipid bolus immediately after a dose of B8 or Diprivan. Results: All formulations except L80 impaired the righting reflex without apparent toxic effects. The authors estimated the threshold dose for induction by determining the x-intercept of the linear regression between time to recovery versus log dose. Threshold doses ranged from 5.8 (95% CI, 5.5 to 6.2) to 8.6 (95% CI, 7.2 to 10.2) mg/kg. A 15 ml/kg lipid bolus resulted in an accelerated clearance. Conclusions: Three of the four novel lipid-free fluoropolymer-based formulations showed efficacy in producing anesthesia, which was comparable to that of Diprivan, and a lipid bolus hastened recovery. These novel propofol formulations have the potential to avoid complications seen with the existing lipid-based formulation.2031-01-0

The molecular basis for Mucosal-Associated Invariant T cell recognition of MR1 proteins

Mucosal-associated invariant T (MAIT) cells are an evolutionarily conserved αβ T-cell lineage that express a semi-invariant T-cell receptor (TCR) restricted to the MHC related-1 (MR1) protein. MAIT cells are dependent upon MR1 expression and exposure to microbes for their development and stimulation, yet these cells can exhibit microbial-independent stimulation when responding to MR1 from different species. We have used this microbial-independent, cross-species reactivity of MAIT cells to define the molecular basis of MAIT-TCR/MR1 engagement and present here a 2.85 Å complex structure of a human MAIT-TCR bound to bovine MR1. The MR1 binding groove is similar in backbone structure to classical peptide-presenting MHC class I molecules (MHCp), yet is partially occluded by large aromatic residues that form cavities suitable for small ligand presentation. The docking of the MAIT-TCR on MR1 is perpendicular to the MR1 surface and straddles the MR1 α1 and α2 helices, similar to classical αβ TCR engagement of MHCp. However, the MAIT-TCR contacts are dominated by the α-chain, focused on the MR1 α2 helix. TCR β-chain contacts are mostly through the variable CDR3β loop that is positioned proximal to the CDR3α loop directly over the MR1 open groove. The elucidation of the MAIT TCR/MR1 complex structure explains how the semi-invariant MAIT-TCR engages the nonpolymorphic MR1 protein, and sheds light onto ligand discrimination by this cell type. Importantly, this structure also provides a critical link in our understanding of the evolution of αβ T-cell recognition of MHC and MHC-like ligands