Climatic change that occurred during the Holocene is often recognized as the main factor for explaining fire dynamics, while the influence of human societies is less apparent. In eastern North ...America, human influence on fire regime before European settlement has been debated, mainly because of a paucity of sites and paleoecological techniques that can distinguish human influences unequivocally from climate. We applied a multiproxy analysis to a 12 000-year-old paleoecological sequence from a site in the vicinity of known settlement areas that were occupied over more than 7000 years. From this analysis, we were able detect the human influence on the fire regime before and after European colonization. Fire occurrence and fire return intervals (FRI) were based on analysis of sedimentary charcoals at a high temporal and spatial resolution. Fire occurrence was then compared to vegetation that was reconstructed from pollen analysis, from population densities deduced from archeological site dating, from demographic and technological models, and from climate reconstructed using general circulation models and ice-core isotopes. Holocene mean FRI was short (164 ± 134 years) and associated with small charcoal peaks that were likely indicative of surface fires affecting small areas. After 1500 BP, large vegetation changes and human demographic growth that was demonstrated through increased settlement evidence likely caused the observed FRI lengthening (301 ± 201 years), which occurred without significant changes in climate. Permanent settlement by Europeans in the area around 1800 AD was followed by a substantial demographic increase, leading to the establishment of Gatineau, Hull and Ottawa. This trend was accompanied by a shift in the charcoal record toward anthropogenic particles that were reflective of fossil fuel burning and an apparent absence of wood charcoal that would be indicative of complete fire suppression. An anthropogenic fire regime that was characterized by severe and large fires and long fire-return intervals occurred more than 1000 years ago, concomitant with the spread of native agriculture, which intensified with European colonization over the past two centuries.
•The Holocene (past 12 000 years) fire regime was compared with trends in vegetation, human demography and climate.•Holocene Fire Return Intervals were short under slow-moving climate, and vegetation and sparse populations.•Late Holocene fire return intervals lengthening tracked demographic growth and vegetation changes.•Past 200 years are characterized by fire suppression and by spherical charcoals indicative of fossil fuel burning.
Normal cells coordinate proliferation and differentiation by precise tuning of gene expression based on the dynamic shifts of the epigenome throughout the developmental timeline. Although ...non-mutational epigenetic reprogramming is an emerging hallmark of cancer, the epigenomic shifts that occur during the transition from normal to malignant cells remain elusive. Here, we capture the epigenomic changes that occur during tumorigenesis in a prototypic embryonal brain tumor, medulloblastoma. By comparing the epigenomes of the different stages of transforming cells in mice, we identify nuclear factor I family of transcription factors, known to be cell fate determinants in development, as oncogenic regulators in the epigenomes of precancerous and cancerous cells. Furthermore, genetic and pharmacological inhibition of NFIB validated a crucial role of this transcription factor by disrupting the cancer epigenome in medulloblastoma. Thus, this study exemplifies how epigenomic changes contribute to tumorigenesis via non-mutational mechanisms involving developmental transcription factors.
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•Dynamic chromatin changes occur along medulloblastoma (MB) formation•Developmental factors NFIA and NFIB act as oncogenes in MB cancer epigenome•Inhibition of NFIB function may enhance molecularly targeted therapy•Epigenomic analyses may identify new targetable oncogenic mechanisms
Shiraishi et al. explored chromatin accessibility in transforming neuronal progenitors into Sonic hedgehog subgroup medulloblastoma, identifying NFI proteins as key regulators of cancer- and cell-cycle-related genes according to their chromatin accessibilities. These findings underscore the significance of cancer epigenomes in promoting oncogenicity through non-mutational developmental transcriptional factors.
Abstract BACKGROUND Constitutive activation of the Sonic Hedgehog (SHH) signaling pathway during cerebellar development may lead to medulloblastoma (MB), one of the most common malignant pediatric ...brain tumor. Clinically, SHH-MB with mutations downstream of SMO or TP53-mutated are a real challenge and alternative targeted therapies are sorely needed for this group of patients. In SHH-MB, the transcription factor Atoh1 is constitutively overexpressed and essential for tumor initiation and progression. Previous work demonstrated that proteasomal-mediated degradation of Atoh1 induces tumor regression in vitro and in vivo, therefore deciphering mechanisms controlling Atoh1 stabilization should provide new avenues for drug development in SHH-MB. METHODS Using a proteomic approach, we identified the deubiquitinating enzyme Usp7 as a positive regulator of Atoh1 in MB cells. We then applied a SILAC-based quantitative ubiquitinomics to investigate the Usp7 target landscape in SHH-MB. We also employed several biochemical approaches to demonstrate the functional interaction between Atoh1 and Usp7 in SHH-MB. In parallel, we validated the impact of Usp7 depletion in vitro and in vivo using relevant SHH-MB models. Last, we investigated large transcriptomic and proteomic datasets to unveil the prognostic value of Usp7 in SHH-MB human tumors. RESULTS We demonstrate that Usp7 binds and accumulates Atoh1 protein by counteracting its ubiquitylation. Post-natal electroporation in vivo directly into the developing cerebella also indicates that overexpression of Usp7 promotes proliferation, whereas in the absence of Atoh1 Usp7 was no longer able to spread cell growth, demonstrating a functional link between the Usp7-Atoh1 axis. In vivo, disruption of Usp7 expression in SHH-MB blocks tumor proliferation. Pharmacological inhibition of Usp7 triggers tumor growth in a syngeneic SHH MB mouse model. Lastly, SHH-MB cells with either TP53 or SMO downstream mutations are sensitive to Usp7 inhibition. CONCLUSIONS Overall, our data pinpoint Usp7 as a promising target against Atoh1, a master regulator of SHH-MB.
Natural peatlands contribute significantly to global carbon sequestration and storage of biomass, most of which derives from Sphagnum peat mosses. Atmospheric CO
levels have increased dramatically ...during the twentieth century, from 280 to > 400 ppm, which has affected plant carbon dynamics. Net carbon assimilation is strongly reduced by photorespiration, a process that depends on the CO
to O
ratio. Here we investigate the response of the photorespiration to photosynthesis ratio in Sphagnum mosses to recent CO
increases by comparing deuterium isotopomers of historical and contemporary Sphagnum tissues collected from 36 peat cores from five continents. Rising CO
levels generally suppressed photorespiration relative to photosynthesis but the magnitude of suppression depended on the current water table depth. By estimating the changes in water table depth, temperature, and precipitation during the twentieth century, we excluded potential effects of these climate parameters on the observed isotopomer responses. Further, we showed that the photorespiration to photosynthesis ratio varied between Sphagnum subgenera, indicating differences in their photosynthetic capacity. The global suppression of photorespiration in Sphagnum suggests an increased net primary production potential in response to the ongoing rise in atmospheric CO
, in particular for mire structures with intermediate water table depths.
While considerable attention has been given to the measurement of mercury (Hg) and lead (Pb) concentrations and accumulation in detailed peat cores in central Canada, the geographic distribution and ...density of sampling are generally limited. Here, we use the Ontario Peatland Inventory to examine broad patterns of Hg and Pb concentration with depth, based on 338 peat cores (containing >1500 analyzed samples) from 127 bogs, fens and swamps located in southeastern, northeastern and northwestern sections of Ontario. Overall, Hg concentrations averaged 0.05 μg g−1 and that of Pb averaged 10.8 μg g−1. Maximum values in the top 50 cm of the profiles are 0.08 μg g−1 and 26.2 μg g−1 for Hg and Pb, respectively. The ratio between these values (surface) and the values from below 100 cm (background), where peat likely accumulated before 1850 and industrial activities were limited, are 2.3 and 6.6 for Hg and Pb, respectively. The highest surface:background concentration ratios are generally found in the westernmost part of the province and in the southeast for Hg and around areas that are more heavily populated for Pb. Our results show that a vast amount of Hg and Pb are stored in Ontarian peatlands, although the spatial distribution of these stores varies. The rapid decomposition of peat in a changing climate could release these pollutants to the atmosphere.
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•Peatlands can record traces of atmospheric pollution.•Hg and Pb concentrations increase in the upper portion of 338 peat profiles sampled within a 450 000 km2 area in Ontario.•The magnitude of increase varies geographically, Hg and Pb showing different patterns.
Ontario peatlands store a considerable amount of lead and mercury, especially in the peat accumulated since industrialization. This storage is spatially variable.
Purpose
We and others have demonstrated that
MYC
-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with ...HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy.
Methods
We used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou–Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment.
Results
MYC
-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of
MYC
amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic
MYC
-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination.
Conclusion
The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood–brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo.
Continuous paleoenvironmental records covering the period prior to the Last Glacial Maximum in northeastern Beringia are sparse. This study presents a multi-proxy analysis of a 35-m-high yedoma ...exposure located on the right bank of the Itkillik River in Alaska. The exposure accumulated over 39thousand years (kyr) during the Middle Wisconsinan Interstadial and the Late Wisconsinan glacial advance. We identified five stratigraphic units based on pollen, carbon and ice content, and isotopic composition (δ18O) of the sediments. Middle Wisconsinan climate in northern Alaska promoted peat accumulation prior to 33.6calkyrBP (calibrated kyr before present). Reconstructed July air temperatures were 1–2°C lower than current at 34.8calkyrBP, consistent with the timing of the interstadial climatic optimum in interior Alaska and Yukon. Colder (by up to 4°C) and drier conditions characterize the transition from interstadial to glacial conditions between 33.6 and 29.8calkyrBP. Late Wisconsinan (29.8–17.9calkyrBP) July air temperatures were 2–3°C lower than today, with grassland vegetation dominated by Poaceae, Artemisia and forbs, in contrast to the modern Cyperaceae dominance. Moister and warmer environmental conditions after 17.9cal kyr BP correspond to the Late Glacial to Early Holocene interval.
•The yedoma-based reconstruction provides insights into the northern Alaska climate over 35ka.•The reconstructed climate fluctuations are consistent with other Beringian records.•Shifts between Cyperaceae and Poaceae pollen mostly drive the reconstruction.
Protein S is a vitamin K–dependent glycoprotein, which, besides its anticoagulant function, acts as an agonist for the tyrosine kinase receptors Tyro3, Axl, and Mer. The endothelium expresses Tyro3, ...Axl, and Mer and produces protein S. The interaction of protein S with endothelial cells and particularly its effects on angiogenesis have not yet been analyzed. Here we show that human protein S, at circulating concentrations, inhibited vascular endothelial growth factor (VEGF) receptor 2–dependent vascularization of Matrigel plugs in vivo and the capacity of endothelial cells to form capillary-like networks in vitro as well as VEGF-A–induced endothelial migration and proliferation. Furthermore, protein S inhibited VEGF-A–induced endothelial VEGFR2 phosphorylation and activation of mitogen-activated kinase-Erk1/2 and Akt. Protein S activated the tyrosine phosphatase SHP2, and the SHP2 inhibitor NSC 87877 reversed the observed inhibition of VEGF-A–induced endothelial proliferation. Using siRNA directed against Tyro3, Axl, and Mer, we demonstrate that protein S-mediated SHP2 activation and inhibition of VEGF-A–stimulated proliferation were mediated by Mer. Our report provides the first evidence for the existence of a protein S/Mer/SHP2 axis, which inhibits VEGFR2 signaling, regulates endothelial function, and points to a role for protein S as an endogenous angiogenesis inhibitor.
Dust is a mineral aerosol of the atmosphere that often contains trace elements such as As, Cd, and Pb. Lhù’ààn Mân’ (Kluane Lake), located in southwestern Yukon, is a region of frequent dust ...activity. In 2016, the lake level fell due to a dramatic decrease in inflow from glacier meltwater, and the delta of the lake became an important source of dust to surrounding ecosystems. To determine the impacts of dust deposition on vegetation and soil trace element concentrations and characteristics, we sampled the lichen Peltigera canina and soil layers at 57 sites along a deposition gradient located 1.4–33.6 km downwind from the principal dust source. Arsenic, Cd, Cu, Ni and Pb in lichens were negatively correlated with the distance away from the dust source, with the highest correlations in Ni and Pb (r2 = 0.50 and 0.48, respectively). Lichen and tree abundances were negatively impacted by dust deposition, suggesting that dust can affect ecosystem vegetation composition. Starting 8 km away from the dust source, the concentrations of As, Ni, and Pb decreased by more than 50% per km, while Cd and Cu concentrations decreased by more than 40% per km. Overall, within the sampled ecosystems, soil pH is 1.4 times higher in the first 8 km from the dust source while carbon content and nutrients are lower, which implies changes in nutrient availability and cycling in dust‐affected ecosystems.
Plain Language Summary
The delta of Lhù’ààn Mân’ (Kluane Lake), located in southwest Yukon and on the traditional lands of Kluane First Nation, Champagne‐Aishihik First Nation, and White River First Nation, is an area where dust often settles and climate change has accelerated the melting of glaciers since the last ice age. Due to reduced glacier water flowing into the lake, the sediments in the delta are more exposed to wind, creating dust storms. To understand the impacts of dust deposition within the surrounding ecosystems, we assessed the levels of trace metals in lichens and soils across a gradient from the delta to the lake. We found that distance from the dust source affected trace metal concentrations in lichens, surface soils, and vegetation. It is essential to understand how these metals spread as they can be potentially toxic and harmful to ecosystems and humans.
Key Points
Dust deposition, indicated by high trace element concentrations, is higher closest to the delta of the Ä’ą̈y Chù’ into Lhù’ààn Mân’
Evidence for dust deposition at Lhù'ààn Mân' can be found in trace elements of the 0–2 cm soil layer and lichens influenced by distance
Vegetation characteristics are impacted by dust deposition more than soil characteristics
Peatlands in northern permafrost regions store a significant proportion of global soil carbon. Recent warming is accelerating peatland permafrost thaw and thermokarst collapse, exposing previously ...frozen peat to microbial decomposition and potential mineralization into greenhouse gases. Here, we show from a site in the sporadic‐discontinuous permafrost zone of western Canada that thermokarst collapse leads to neither large losses nor gains following thaw, as deep carbon losses are offset by surficial accumulation. We collected peat cores along two thaw chronosequences, from peat plateau, through young (~30 years since thaw), intermediate (~70 years), and mature (~200 years) thermokarst bog locations. Macrofossil and 14C analysis showed synchronicity of peatland development until recent thaw, with wetland initiation ~8,500 cal yr BP followed by succession through peatland stages prior to permafrost aggradation ~1,800 cal yr BP. Analysis and modeling of soil carbon stocks indicated 8.7 ± 12.4 kg C m−2 of carbon accumulated prior to thaw was lost in ~200 years post‐thaw. Despite these losses, there was no observed increase in peat humification as assessed by Fourier transform infrared and C:N ratios. Rapid peat accumulation post‐thaw (9.8 ± 1.6 kg C m−2 over 200 years) offset deeper losses. Our approach constrains the net carbon balance to be between uptake of 27.3 g C m−2 yr−1 and loss of 106.6 g C m−2 yr−1 over 200 years post‐thaw. While our approach cannot determine whether thermokarst bogs in the sporadic‐discontinuous permafrost zone act as long‐term carbon sinks or sources post‐thaw, our study better constrains post‐thaw C losses and gains.
Plain Language Summary
Northern peatlands store a third of the world's soil carbon, a store which has slowly accumulated over the last 10,000 years. A large amount of this soil carbon has become frozen in permafrost peatlands, but warming is causing these stores to thaw. Permafrost thaw in peatlands not only leads to potential decomposition of previously frozen peat but also leads to increased growth of mosses at the surface. Increased decomposition of previously frozen peat can release formerly trapped carbon into the atmosphere as greenhouse gases, thus accelerating ongoing climate warming, while increased moss growth would increase carbon storage. In this study, we investigated the long‐term impact of thawing on peatland carbon storage. To do this, we measured the amount of previously frozen permafrost carbon that was lost following thaw and compared it to the amount that accumulated at the surface. We found no long‐term net impact of permafrost thaw on carbon stores, as losses of previously frozen carbon were offset by carbon that accumulated at the surface following thaw. Our results rule out both large rapid losses and large gains of carbon following thaw in peatlands, which greatly help to constrain projections of carbon cycling at high latitudes in a warming world.
Key Points
We used a chronosequence approach to assess the long‐term impact of permafrost thaw on peatland carbon stores
Losses of deep carbon offset by accumulation at the surface following thaw
We rule out large losses and gains of carbon following permafrost thaw at a site with a history of epigenetic permafrost aggradation
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