The WWTR1 (protein is known as TAZ) -CAMTA1 (WC) fusion gene defines epithelioid hemangioendothelioma, a malignant vascular cancer. TAZ (transcriptional coactivator with PDZ binding motif) is a transcriptional coactivator and end effector of the Hippo tumor suppressor pathway. It is inhibited by phosphorylation by the Hippo kinases LATS1 and LATS2. Such phosphorylation causes cytoplasmic localization, 14-3-3 protein binding and the phorphorylation of a terminal phosphodegron promotes ubiquitin-dependent degradation (the phosphorylation of the different motifs has several effects). CAMTA1 is a putative tumor suppressive transcription factor. Here we demonstrate that TAZ-CAMTA1 (TC) fusion results in its nuclear localization and constitutive activation. Consequently, cells expressing TC display a TAZ-like transcriptional program that causes resistance to anoikis and oncogenic transformation. Our findings elucidate the mechanistic basis of TC oncogenic properties, highlight that TC is an important model to understand how the Hippo pathway can be inhibited in cancer, and provide approaches for targeting this chimeric protein.

Maximal resection of tumor while preserving the adjacent healthy tissue is particularly important for larynx surgery, hence precise and rapid intraoperative histology of laryngeal tissue is crucial for providing optimal surgical outcomes. We hypothesized that deep-learning based stimulated Raman scattering (SRS) microscopy could provide automated and accurate diagnosis of laryngeal squamous cell carcinoma on fresh, unprocessed surgical specimens without fixation, sectioning or staining. Methods : We first compared 80 pairs of adjacent frozen sections imaged with SRS and standard hematoxylin and eosin histology to evaluate their concordance. We then applied SRS imaging on fresh surgical tissues from 45 patients to reveal key diagnostic features, based on which we have constructed a deep learning based model to generate automated histologic results. 18,750 SRS fields of views were used to train and cross-validate our 34-layered residual convolutional neural network, which was used to classify 33 untrained fresh larynx surgical samples into normal and neoplasia. Furthermore, we simulated intraoperative evaluation of resection margins on totally removed larynxes. Results : We demonstrated near-perfect diagnostic concordance (Cohen's kappa, κ > 0.90) between SRS and standard histology as evaluated by three pathologists. And deep-learning based SRS correctly classified 33 independent surgical specimens with 100% accuracy. We also demonstrated that our method could identify tissue neoplasia at the simulated resection margins that appear grossly normal with naked eyes. Conclusion : Our results indicated that SRS histology integrated with deep learning algorithm provides potential for delivering rapid intraoperative diagnosis that could aid the surgical management of laryngeal cancer.

Abstract. We conduct a global inverse analysis of 2010–2018 GOSAT observations to better understand the factors controlling atmospheric methane and its accelerating increase over the 2010–2018 period. The inversion optimizes anthropogenic methane emissions and their 2010–2018 trends on a 4∘×5∘ grid, monthly regional wetland emissions, and annual hemispheric concentrations of tropospheric OH (the main sink of methane). We use an analytical solution to the Bayesian optimization problem that provides closed-form estimates of error covariances and information content for the solution. We verify our inversion results with independent methane observations from the TCCON and NOAA networks. Our inversion successfully reproduces the interannual variability of the methane growth rate inferred from NOAA background sites. We find that prior estimates of fuel-related emissions reported by individual countries to the United Nations are too high for China (coal) and Russia (oil and gas) and too low for Venezuela (oil and gas) and the US (oil and gas). We show large 2010–2018 increases in anthropogenic methane emissions over South Asia, tropical Africa, and Brazil, coincident with rapidly growing livestock populations in these regions. We do not find a significant trend in anthropogenic emissions over regions with high rates of production or use of fossil methane, including the US, Russia, and Europe. Our results indicate that the peak methane growth rates in 2014–2015 are driven by low OH concentrations (2014) and high fire emissions (2015), while strong emissions from tropical (Amazon and tropical Africa) and boreal (Eurasia) wetlands combined with increasing anthropogenic emissions drive high growth rates in 2016–2018. Our best estimate is that OH did not contribute significantly to the 2010–2018 methane trend other than the 2014 spike, though error correlation with global anthropogenic emissions limits confidence in this result.

Abstract. We use satellite (GOSAT) and in situ (GLOBALVIEWplus CH4 ObsPack) observations of atmospheric methane in a joint global inversion of methane sources, sinks, and trends for the 2010–2017 period. The inversion is done by analytical solution to the Bayesian optimization problem, yielding closed-form estimates of information content to assess the consistency and complementarity (or redundancy) of the satellite and in situ data sets. We find that GOSAT and in situ observations are to a large extent complementary, with GOSAT providing a stronger overall constraint on the global methane distributions, but in situ observations being more important for northern midlatitudes and for relaxing global error correlations between methane emissions and the main methane sink (oxidation by OH radicals). The in-situ-only and the GOSAT-only inversions alone achieve 113 and 212 respective independent pieces of information (DOFS) for quantifying mean 2010–2017 anthropogenic emissions on 1009 global model grid elements, and respective DOFS of 67 and 122 for 2010–2017 emission trends. The joint GOSAT+ in situ inversion achieves DOFS of 262 and 161 for mean emissions and trends, respectively. Thus, the in situ data increase the global information content from the GOSAT-only inversion by 20 %–30 %. The in-situ-only and GOSAT-only inversions show consistent corrections to regional methane emissions but are less consistent in optimizing the global methane budget. The joint inversion finds that oil and gas emissions in the US and Canada are underestimated relative to the values reported by these countries to the United Nations Framework Convention on Climate Change (UNFCCC) and used here as prior estimates, whereas coal emissions in China are overestimated. Wetland emissions in North America are much lower than in the mean WetCHARTs inventory used as a prior estimate. Oil and gas emissions in the US increase over the 2010–2017 period but decrease in Canada and Europe. The joint inversion yields a global methane emission of 551 Tg a−1 averaged over 2010–2017 and a methane lifetime of 11.2 years against oxidation by tropospheric OH (86 % of the methane sink).

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Abstract. We conduct a global inverse analysis of 2010–2018 GOSAT satellite observations to better understand the factors controlling atmospheric methane and its accelerating increase over the 2010–2018 period. The inversion optimizes 2010–2018 anthropogenic methane emissions and their trends on a 4º × 5º grid, monthly regional wetland emissions, and annual hemispheric concentrations of tropospheric OH (the main sink of methane) also for individual years. We use an analytical solution to the Bayesian optimization problem that provides closed-form estimates of error covariances and information content for the solution. Our inversion successfully reduces the errors against the independent methane observations from the TCCON network and reproduces the interannual variability of the methane growth rate inferred from NOAA background sites. We find that prior estimates of fuel-related emissions reported by individual countries to the United Nations are too high for China (coal) and Russia (oil/gas), and too low for Venezuela (oil/gas) and the U.S. (oil/gas). We show that the 2010–2018 increase in global methane emissions is mainly driven by tropical wetlands (Amazon and tropical Africa), boreal wetlands (Eurasia), and tropical livestock (South Asia, Africa, Brazil), with no significant trend in oil/gas emissions. While the rise in tropical livestock emissions is consistent with bottom-up estimates of rapidly growing cattle populations, the rise in wetland emissions needs to be better understood. The sustained acceleration of growth rates in 2016–2018 relative to 2010–2013 is mostly from wetlands, while the peak methane growth rates in 2014–2015 are also contributed by low OH concentrations (2014) and high fire emissions (2015). Our best estimate is that OH did not contribute significantly to the 2010–2018 methane trend other than the 2014 spike, though error correlation with global anthropogenic emissions limits confidence in this result.

Abstract. We use optimal estimation (OE) to quantify methane fluxes based on total column CH4 data from the Greenhouse Gases Observing Satellite (GOSAT) and the GEOS-Chem global chemistry transport model. We then project these fluxes to emissions by sector at 1∘ resolution and then to each country using a new Bayesian algorithm that accounts for prior and posterior uncertainties in the methane emissions. These estimates are intended as a pilot dataset for the global stock take in support of the Paris Agreement. However, differences between the emissions reported here and widely used bottom-up inventories should be used as a starting point for further research because of potential systematic errors of these satellite-based emissions estimates. We find that agricultural and waste emissions are ∼ 263 ± 24 Tg CH4 yr−1, anthropogenic fossil emissions are 82 ± 12 Tg CH4 yr−1, and natural wetland/aquatic emissions are 180 ± 10 Tg CH4 yr−1. These estimates are consistent with previous inversions based on GOSAT data and the GEOS-Chem model. In addition, anthropogenic fossil estimates are consistent with those reported to the United Nations Framework Convention on Climate Change (80.4 Tg CH4 yr−1 for 2019). Alternative priors can be easily tested with our new Bayesian approach (also known as prior swapping) to determine their impact on posterior emissions estimates. We use this approach by swapping to priors that include much larger aquatic emissions and fossil emissions (based on isotopic evidence) and find little impact on our posterior fluxes. This indicates that these alternative inventories are inconsistent with our remote sensing estimates and also that the posteriors reported here are due to the observing and flux inversion system and not uncertainties in the prior inventories. We find that total emissions for approximately 57 countries can be resolved with this observing system based on the degrees-of-freedom for signal metric (DOFS > 1.0) that can be calculated with our Bayesian flux estimation approach. Below a DOFS of 0.5, estimates for country total emissions are more weighted to our choice of prior inventories. The top five emitting countries (Brazil, China, India, Russia, USA) emit about half of the global anthropogenic budget, similar to our choice of prior emissions but with the posterior emissions shifted towards the agricultural sector and less towards fossil emissions, consistent with our global posterior results. Our results suggest remote-sensing-based estimates of methane emissions can be substantially different (although within uncertainty) than bottom-up inventories, isotopic evidence, or estimates based on sparse in situ data, indicating a need for further studies reconciling these different approaches for quantifying the methane budget. Higher-resolution fluxes calculated from upcoming satellite or aircraft data such as the Tropospheric Monitoring Instrument (TROPOMI) and those in formulation such as the Copernicus CO2M, MethaneSat, or Carbon Mapper can be incorporated into our Bayesian estimation framework for the purpose of reducing uncertainty and improving the spatial resolution and sectoral attribution of subsequent methane emissions estimates.

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