PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors.

Necroptosis, a form of regulated necrotic cell death, is governed by RIP1/RIP3-mediated activation of MLKL. However, the signaling process leading to necroptotic death remains to be elucidated. In this study, we found that PUMA, a proapoptotic BH3-only Bcl-2 family member, is transcriptionally activated in an RIP3/MLKL-dependent manner following induction of necroptosis. The induction of PUMA, which is mediated by autocrine TNF-α and enhanced NF-κB activity, contributes to necroptotic death in RIP3-expressing cells with caspases inhibited. On induction, PUMA promotes the cytosolic release of mitochondrial DNA and activation of the DNA sensors DAI/Zbp1 and STING, leading to enhanced RIP3 and MLKL phosphorylation in a positive feedback loop. Furthermore, deletion of PUMA partially rescues necroptosis-mediated developmental defects in FADD-deficient embryos. Collectively, our results reveal a signal amplification mechanism mediated by PUMA and cytosolic DNA sensors that is involved in TNF-driven necroptotic death in vitro and in vivo

Spatial and Temporal Variations in Extreme Precipitation and Temperature Events in the Beijing–Tianjin–Hebei Region of China over the Past Six Decades

Extreme weather events can cause a lot of damage in highly populated regions, such as in the Beijing–Tianjin–Hebei Region (BTHR) in northern China. To understand where and how extreme precipitation and temperature events are changing within the BTHR, data for 1959–2018 from 25 mereological stations were used to detect trends in the intensity, frequency, and duration of these events. The results showed that intensity, accumulated amount, the duration of extreme precipitation events, and the annual number of days with precipitation greater than 50 mm decreased on a regional scale over this 60-year period. Changes in extreme precipitation events at most stations were not statistically significant, although a few stations had a significant downward trend. The combined effects of the East Asian summer monsoon and rapid urbanization are possible reasons for these trends. Both the annual maximum and minimum temperature increased on a regional and local scale. The frequency of extreme hot and cold weather also, respectively, increased and decreased, with consistent patterns on a regional and local scale. However, the spatial changes of these trends were different, reflecting the effects of irrigation and urbanization on the regional surface energy balance. These findings are valuable to decisionmakers involved in disaster prevention in the BTHR and in other highly populated regions worldwide

Well-to-wheels total energy and GHG emissions of HCNG heavy-duty vehicles in China: Case of EEV qualified EURO 5 emissions scenario

Energy security and climate change are critical concerns in the present era. The booming of the vehicle population has worsened the environment and has caused severe air pollution problems, especially in urban areas. The utilization of hydrogen-enriched compressed natural gas in internal combustion engines shows abundant prospects for improved performance and reduced on-road emissions of greenhouse gases and air pollutants. This study aims to provide an insight to well-to-wheels environmental implications of the 20% HCNG fuel mixture in terms of total energy use, and greenhouse gas emissions per megajoules (MJ) of thermal energy output. The well-to-tank (WTT) impacts were evaluated using GREET 1 (2017). GREET 1 is a fuel cycle modeling tool developed by 'Argonne national laboratory.' GREET (R) is extensively used by researchers worldwide to analytically simulate energy use and emission output of various vehicle and fuel combinations. This study uses 12 prospective pathways of gaseous hydrogen production for analysis purposes. In the tank-to-wheels (TTW) phase, the 20%HCNG@EEV reduces the brake specific energy consumption (BSEC) by approximately 5%, and also decreases GHG emissions by 14% compared with 0%HCNG@EURO3. For simplicity, EURO5 is entitled as 'EEV' and has been excluded in most of the discussion, only highlighting 'EEV,' which abbreviates as 'Enhanced Environmentally friendly Vehicles.' For the entire well-to-wheels phase, this research work shows that all of the 20%HCNG@EEV pathways have lower total energy use and GHG emissions than 0%HCNG@EURO3 except the two pathways, such as grid electricity-to-hydrogen (without CO2 sequestration) and coal gasification-to-hydrogen (without CO2 sequestration). The WTW total energy and GHG emissions reduced by approximately 14% and 13%, respectively, with 20%HCNG@EEV based on the coke oven gas pathway compared with 0%HCNG@EURO3. It is essential to note that the use of cleaner feedstock for hydrogen, such as power-to-gas (P2G), biomass, coke oven gas (by-product), and natural gas shows tremendous prospects for realizing and practicing sustainable `hydrogen economy' in China. Further technological advancement and reduction in total costs of HCNG utilization in powertrains will increase the number of HCNG vehicles decreasing the burden of air pollution, climate change, and energy crisis threats. (C) 2020 Hydrogen Energy Publications LLC. Published by Elsevier Ltd. All rights reserved

Synthetical lethality of Werner helicase and mismatch repair deficiency is mediated by p53 and PUMA in colon cancer

Synthetic lethality is a powerful approach for targeting oncogenic drivers in cancer. Recent studies revealed that cancer cells with microsatellite instability (MSI) require Werner (WRN) helicase for survival; however, the underlying mechanism remains unclear. In this study, we found that WRN depletion strongly induced p53 and its downstream apoptotic target PUMA in MSI colorectal cancer (CRC) cells. p53 or PUMA deletion abolished apoptosis induced by WRN depletion in MSI CRC cells. Importantly, correction of MSI abrogated the activation of p53/PUMA and cell killing, while induction of MSI led to sensitivity in isogenic CRC cells. Rare p53-mutant MSI CRC cells are resistant to WRN depletion due to lack of PUMA induction, which could be restored by wildtype (WT) p53 knock in or reconstitution. WRN depletion or treatment with the RecQ helicase inhibitor ML216 suppressed in vitro and in vivo growth of MSI CRCs in a p53/PUMA-dependent manner. ML216 treatment was efficacious in MSI CRC patient-derived xenografts. Interestingly, p53 gene remains WT in the majority of MSI CRCs. These results indicate a critical role of p53/PUMA-mediated apoptosis in the vulnerability of MSI CRCs to WRN loss, and support WRN as a promising therapeutic target in p53-WT MSI CRCs.Fil: Hao, Suisui. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados UnidosFil: Tong, Jingshan. UPMC Hillman Cancer Center; Estados Unidos. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Jha, Anupma. UPMC Hillman Cancer Center; Estados UnidosFil: Risnik, Denise Mariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados UnidosFil: Lizardo, Darleny. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados UnidosFil: Lu, Xinyan. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados UnidosFil: Goel, Ajay. Beckman Research Institute of City of Hope Comprehensive Cancer Center; Reino UnidoFil: Opresko, Patricia L.. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados UnidosFil: Yu, Jian. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados UnidosFil: Zhang, Lin. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. UPMC Hillman Cancer Center; Estados Unido

CDK4/6 inhibition suppresses p73 phosphorylation and activates DR5 to potentiate chemotherapy and immune checkpoint blockade

Targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is a successful therapeutic approach against breast and other solid tumors. Inhibition of CDK4/6 halts cell cycle progression and promotes antitumor immunity. However, the mechanisms underlying the antitumor activity of CDK4/6 inhibitors are not fully understood. We found that CDK4/6 bind and phosphorylate the p53 family member p73 at threonine 86, which sequesters p73 in the cytoplasm. Inhibition of CDK4/6 led to dephosphorylation and nuclear translocation of p73, which transcriptionally activated death receptor 5 (DR5), a cytokine receptor and key component of the extrinsic apoptotic pathway. p73-mediated induction of DR5 by CDK4/6 inhibitors promoted immunogenic cell death of cancer cells. Deletion of DR5 in cancer cells in vitro and in vivo abrogated the potentiating effects of CDK4/6 inhibitors on immune cytokine TRAIL, 5-fluorouracil chemotherapy, and anti–PD-1 immunotherapy. Together, these results reveal a previously unrecognized consequence of CDK4/6 inhibition, which may be critical for potentiating the killing and immunogenic effects on cancer cells.Fil: Tong, Jingshan. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Tan, Xiao. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Song, Xiangping. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Gao, Man. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Risnik, Denise Mariel. Univeristy of Pittsburgh. School of Medicine; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Hao, Suisui. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Ermine, Kaylee. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Wang, Peng. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Li, Hua. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Huang, Yi. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Yu, Jian. Univeristy of Pittsburgh. School of Medicine; Estados UnidosFil: Zhang, Lin. Univeristy of Pittsburgh. School of Medicine; Estados Unido