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Changes in fire regimes since the Last Glacial Maximum: an assessment based on a global synthesis and analysis of charcoal data(2008) Power, M; Marlon, J; Ortiz, N; Bartlein, P; Harrison, Simon; Mayle, F; Ballouche, A; Bradshaw, R; Carcaillet, C; Cordova, C; Mooney, Scott; Moreno, P; Prentice, I; Thonicke, K; Tinner, W; Whitlock, C; Zhang, Yanling; Zhao, Yong; Ali, Amna; Anderson, Richard; Beer, R; Behling, H; Briles, C; Brown, Katherine; Brunelle, A; Bush, M; Camill, P; Chu, G; Clark, J; Colombaroli, D; Connor, Stuart; Daniau, A; Daniels, M; Dodson, John; Doughty, E; Edwards, Meredith; Finsinger, W; Foster, Douglas; Frechette, J; Gaillard, M; Gavin, D; Gobet, E; Haberle, Simon; Hallett, D; Higuera, P; Hope, G; Horn, S; Inoue, J; Kaltenrieder, P; Kennedy, Liz; Kong, Z; Larsen, C; Long, C; Lynch, Jodi; Lynch, E; McGlone, M; Meeks, S; Mensing, S; Meyer, G; Minckley, T; Mohr, J; Nelson, D; New, J; Newnham, R; Noti, R; Oswald, W; Pierce, J; Richard, P; Rowe, C; Goni, M; Shuman, B; Takahara, H; Toney, J; Turney, C; Urrego-Sanchez, D; Umbanhowar, C; Vandergoes, M; Vanniere, B; Vescovi, EJournal ArticleFire activity has varied globally and continuously since the last glacial maximum (LGM) in response to long-term changes in global climate and shorter-term regional changes in climate, vegetation, and human land use. We have synthesized sedimentary charcoal records of biomass burning since the LGM and present global maps showing changes in fire activity for time slices during the past 21,000 years (as differences in charcoal accumulation values compared to pre-industrial). There is strong broad-scale coherence in fire activity after the LGM, but spatial heterogeneity in the signals increases thereafter. In North America, Europe and southern South America, charcoal records indicate less-than-present fire activity during the deglacial period, from 21,000 to ∼11,000 cal yr BP. In contrast, the tropical latitudes of South America and Africa show greater-than-present fire activity from ∼19,000 to ∼17,000 cal yr BP and most sites from Indochina and Australia show greater-than-present fire activity from 16,000 to ∼13,000 cal yr BP. Many sites indicate greater-than-present or near-present activity during the Holocene with the exception of eastern North America and eastern Asia from 8,000 to ∼3,000 cal yr BP, Indonesia and Australia from 11,000 to 4,000 cal yr BP, and southern South America from 6,000 to 3,000 cal yr BP where fire activity was less than present. Regional coherence in the patterns of change in fire activity was evident throughout the post-glacial period. These complex patterns can largely be explained in terms of large-scale climate controls modulated by local changes in vegetation and fuel load.
(2022) Kokkinos, JohnThesisLess than 10% of patients with pancreatic ductal adenocarcinoma (PDAC) survive more than 5 years. One of the characteristic features that drive the aggressive nature of PDAC is its multicellular, heterogeneous, and fibrotic microenvironment. We previously identified a cytoskeletal protein, βIII-tubulin, as a novel therapeutic target in PDAC. However, the PDAC cell survival mechanisms controlled by βIII-tubulin were previously unknown. We also identified a major gap in the ability of human PDAC preclinical models to accurately mimic the 3D multicellular architecture and stroma of the disease. Thus, the aims of this work were (1) to evaluate the pro-survival role of βIII-tubulin in PDAC; (2) to establish a new patient derived tumour explant model that maintains all features of the PDAC microenvironment; and (3) to use the tumour explant model to test the clinical potential of silencing βIII-tubulin expression as well as two stromal targets that had been previously explored by our lab: solute carrier 7A11 (SLC7A11) and heat shock protein 47 (HSP47) Here, we identified that silencing βIII-tubulin in pancreatic cancer cells activated extrinsic apoptosis and increased their sensitivity to extrinsic apoptosis inducers including tumour necrosis factor-α (TNFα), Fas-ligand (FasL), and TNF-related apoptosis inducing factor (TRAIL). We next established the patient derived PDAC tumour explant model. We cultured whole-tissue tumour explants from PDAC patients for 12 days and demonstrated that explants maintained their 3D multicellular architecture, proliferative state, and collagen fibrosis. We also demonstrated the ability to deliver chemotherapeutics and siRNA-nanoparticles to the tumour explants. Finally, we tested the utility of this model to investigate the clinical potential of silencing three different therapeutic targets. We showed that therapeutic silencing of βIII-tubulin combined with TRAIL increased extrinsic apoptosis, decreased cell proliferation, and decreased tumour cell number. Inhibition of the stromal target SLC7A11 reduced tumour cell number and inhibited activity of stromal cancer-associated fibroblasts. Silencing of another target, HSP47, also led to a reduction in tumour cells and decreased cell proliferation. Overall, this work has discovered a previously unexplored role of βIII-tubulin as a brake on extrinsic cell death and has developed a new human PDAC preclinical model with utility in the drug development and precision medicine pipeline.