Brockstender8977

S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common group of cancers in the world, and patients have a poor prognosis. Here, we present data indicating that YAP1 may be a strong driver of the onset and progression of oral SCC (OSCC), a major subtype of HNSCC. Mice with tongue-specific deletion of Mob1a/b and thus endogenous YAP1 hyperactivation underwent surprisingly rapid and highly reproducible tumorigenesis, developing tongue carcinoma in situ within 2 weeks and invasive SCC within 4 weeks. In humans, precancerous tongue dysplasia displays YAP1 activation correlating with reduced patient survival. Combinations of molecules mutated in OSCC may increase and sustain YAP1 activation to the point of oncogenicity. Strikingly, siRNA or pharmacological inhibition of YAP1 blocks murine OSCC onset in vitro and in vivo. Our work justifies targeting YAP1 as therapy for OSCC and perhaps HNSCC, and our mouse model represents a powerful tool for evaluating these agents. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).Independent verification of anthropogenic influence on specific extreme climate events remains elusive. This study presents a framework for such verification. This framework reveals that previously published results based on a 1961-2005 attribution period frequently underestimate the influence of global warming on the probability of unprecedented extremes during the 2006-2017 period. This underestimation is particularly pronounced for hot and wet events, with greater uncertainty for dry events. The underestimation is reflected in discrepancies between probabilities predicted during the attribution period and frequencies observed during the out-of-sample verification period. These discrepancies are most explained by increases in climate forcing between the attribution and verification periods, suggesting that 21st-century global warming has substantially increased the probability of unprecedented hot and wet events. Hence, the use of temporally lagged periods for attribution-and, more broadly, for extreme event probability quantification-can cause underestimation of historical impacts, and current and future risks. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).The relationship between microscopic observations and macroscopic behavior is a fundamental open question in biophysical systems. Here, we develop a unified approach that-in contrast with existing methods-predicts cell type from macromolecular data even when accounting for the scale of human tissue diversity and limitations in the available data. We achieve these benefits by applying a k-nearest-neighbors algorithm after projecting our data onto the eigenvectors of the correlation matrix inferred from many observations of gene expression or chromatin conformation. Our approach identifies variations in epigenotype that affect cell type, thereby supporting the cell-type attractor hypothesis and representing the first step toward model-independent control strategies in biological systems. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).Neoantigen vaccines have been enthusiastically pursued for personalized cancer immunotherapy while vast majority of neoantigens have no or low immunogenicity. Here, a bi-adjuvant neoantigen nanovaccine (banNV) that codelivered a peptide neoantigen (Adpgk) with two adjuvants [Toll-like receptor (TLR) 7/8 agonist R848 and TLR9 agonist CpG] was developed for potent cancer immunotherapy. Specifically, banNVs were prepared by a nanotemplated synthesis of concatemer CpG, nanocondensation with cationic polypeptides, and then physical loading with hydrophobic R848 and Adpgk. The immunogenicity of the neoantigen was profoundly potentiated by efficient codelivery of neoantigen and dual synergistic adjuvants, which is accompanied by reduced acute systemic toxicity. Linsitinib in vitro BanNVs sensitized immune checkpoint programmed death receptor 1 (PD-1) on T cells, therefore, a combination of banNVs with aPD-1 conspicuously induced the therapy response and led to complete regression of 70% neoantigen-specific tumors without recurrence. We conclude that banNVs are promising to optimize personalized therapeutic neoantigen vaccines for cancer immunotherapy. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).Atmospheric nitrogen (N) deposition affects the greenhouse gas (GHG) balance of ecosystems through the net atmospheric CO2 exchange and the emission of non-CO2 GHGs (CH4 and N2O). We quantified the effects of N deposition on biomass increment, soil organic carbon (SOC), and N2O and CH4 fluxes and, ultimately, the net GHG budget at ecosystem level of a Moso bamboo forest in China. Nitrogen addition significantly increased woody biomass increment and SOC decomposition, increased N2O emission, and reduced soil CH4 uptake. Despite higher N2O and CH4 fluxes, the ecosystem remained a net GHG sink of 26.8 to 29.4 megagrams of CO2 equivalent hectare-1 year-1 after 4 years of N addition against 22.7 hectare-1 year-1 without N addition. The total net carbon benefits induced by atmospheric N deposition at current rates of 30 kilograms of N hectare-1 year-1 over Moso bamboo forests across China were estimated to be of 23.8 teragrams of CO2 equivalent year-1. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.