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Abstract The frequency, intensity, and duration of extreme heatwaves are projected to increase in the global context of climate change. However, evidence of how anthropogenic emissions respond to heatwaves and further impact air quality remains elusive. Here, we use satellite remote sensing measurements alongside chemical transport model simulations to reveal abrupt variations in primary and secondary air pollutants introduced by extreme heatwaves. We highlight evidence from China and India, where satellite sulfur dioxide (SO2) and nitrogen dioxide (NO2) columns over thermal power plants enhance consistently responding to heatwaves. We attribute such spiked emissions to soaring electricity use and demonstrate that bottom‐up inventories underestimate the emissions from the power sector by 34.9% for the selected case. Elevated emissions facilitate fine particulate matter (PM2.5) and ozone (O3) formation over thermal power plants in an inhomogeneous manner, due to the combined effect of atmospheric oxidizing capacity, thermal decomposition of peroxyacetyl nitrate, planetary boundary layer rise, and air stagnation. Our results underscore the emerging challenge of pollution control attributable to the increasing climate penalty and the necessity of targeted control strategies and alternative energy sources during heatwaves.

Abstract Non‐methane volatile organic compounds (NMVOCs) have a significant impact on air quality in urban areas. Detecting NMVOCs emission with its proxy HCHO on urban scales from space, however, has been limited by the lack of discernible enhancement. Here we show clear urban HCHO plumes from 16 cities over the globe by rotating TROPOspheric Monitoring Instrument HCHO pixels according to wind directions. We fit the downwind structure of the plumes with the exponentially modified Gaussian approach to quantify urban HCHO effective production rates between 7.0 and 88.5 mol s−1. Our results are in line with total NMVOC emissions from the EDGAR inventory (r = 0.76). Our work offers a new measure of total NMVOC emissions from urban areas and highlights the potential of satellite HCHO data to provide new information for monitoring urban air quality.

Abstract Emissions of air pollutants and their precursors in urban air closely relate to urbanization involving economic development, population growth, and industrialization. Here we use formaldehyde (HCHO) columns from the TROPOspheric Monitoring Instrument (TROPOMI), night‐time light (NTL) radiance from the Visible Infrared Imaging Radiometer Suite, and population density data as respective proxies to explore how anthropogenic non‐methane volatile organic compound (NMVOC) emissions evolve with urbanization in Asia. HCHO columns correlate moderately to highly (0.64 ≤ r ≤ 0.99) with the NTL radiance within most major Asian countries. On both national (across Asia) and provincial scales (within China), HCHO columns increase monotonically with NTL radiance or population density with a log‐linear pattern, implying anthropogenic NMVOC emissions in Asia may similarly respond to urbanization with no apparent turnover yet. Our study confirms TROPOMI HCHO columns as a proxy of anthropogenic NMVOC emissions.

Abstract Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function‐2 through the residues Phe737 and Gln738. Without ligand or with agonist binding, H12 swings from inward to outward to visit different folding positions. However, the binding of RU486 or AZD9567 perturbs the structural state, and the passive antagonist state appears more stable. Structure‐based virtual screening and in vitro bioassays are used to discover novel GR ligands that bias the conformation equilibria toward the passive antagonist state. HP‐19 exhibits the best anti‐inflammatory activity (IC50 = 0.041 ± 0.011 µm) in nuclear factor‐kappa B signaling pathway, which is comparable to that of DEX. HP‐19 also does not induce adverse effect‐related transactivation functions of GR. The novel ligands discovered here may serve as promising starting points for the development of GR modulators.

Aberrant fibroblast growth factor receptor-1 (FGFR1), a key driver promoting gastric cancer (GC) progression and chemo-resistance, has been increasingly recognized as a potential therapeutic target in GC. Hereon, we designed and synthesized a series of asymmetric analogues using Af23 and NDGA as lead compounds by retaining the basic structural framework (bisaryl-1,4-dien-3-one) and the unilateral active functional groups (3,4-dihydroxyl). Thereinto, Y14 showed considerable inhibitory activity against FGFR1. Next, pharmacological experiments showed that Y14 could significantly inhibit the phosphorylation of FGFR1 and its downstream kinase AKT and ERK, thus inhibiting the growth, survival, and migration of gastric cancer cells. Furthermore, compared with 5-FU treatment alone, the combination of Y14 and 5-FU significantly reduced the phosphorylation level of FGFR1, and enhanced the anti-cancer effect by inhibiting the viability and colony formation in two gastric cancer cell lines. These results confirmed that Y14 exerted anti-gastric activity and chemosensitizing effect by inhibiting FGFR1 phosphorylation and its downstream signaling pathway in vitro. This work also provides evidence that Y14, an effective FGFR1 inhibitor, could be used alone or in combination with chemotherapy to treat gastric cancer in the future.

Androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of many severe diseases such as prostate cancer, muscle atrophy, and osteoporosis. Binding of ligands to AR triggers the conformational changes in AR that may affect the recruitment of coactivators and downstream response of AR signaling pathway. Therefore, AR ligands have great potential to treat these diseases. In this study, we searched for novel AR ligands by performing a docking-based virtual screening (VS) on the basis of the crystal structure of the AR ligand binding domain (LBD) in complex with its agonist. A total of 58 structurally diverse compounds were selected and subjected to LBD affinity assay, with five of them (HBP1-3, HBP1-17, HBP1-38, HBP1-51, and HBP1-58) exhibiting strong binding to AR-LBD. The IC50 values of HBP1-51 and HBP1-58 are 3.96 µM and 4.92 µM, respectively, which are even lower than that of enzalutamide (Enz, IC50 = 13.87 µM), a marketed second-generation AR antagonist. Further bioactivity assays suggest that HBP1-51 is an AR agonist, whereas HBP1-58 is an AR antagonist. In addition, molecular dynamics (MD) simulations and principal components analysis (PCA) were carried out to reveal the binding principle of the newly-identified AR ligands toward AR. Our modeling results indicate that the conformational changes of helix 12 induced by the bindings of antagonist and agonist are visibly different. In summary, the current study provides a highly efficient way to discover novel AR ligands, which could serve as the starting point for development of new therapeutics for AR-related diseases. Keywords: Androgen receptor, AR ligand, Virtual screening, AR agonist, AR antagonist

The free fatty acid-mediated inflammatory activities are regulated through TLR4. Here the authors show that palmitic acid binds to MD2, initiating complex formation with TLR4, recruitment of MyD88, and subsequent activation of pro-inflammatory molecules, and that MD2 blockade protects against diet-induced cardiac dysfunction.

Nature Communications 8: Article number: 13997 (2017); Published: 3 January 2017; Updated: 19 March 2018 The original version of this Article contained an error in the Methods section entitled ‘Fatty acid-albumin complex’, where the bovine serum albumin concentration of the 5 mM palmitic acid solution used for in vitro experiments was incorrectly reported as being 28 μM, and should have read 627 μM.

The applications of geostationary (GEO) satellite measurements at an unprecedented spatial and temporal resolution from the Geostationary Environment Monitoring Spectrometer (GEMS) for monitoring and forecasting the alarming ozone pollution in Asia through data assimilation remain at the early stage. Here we investigate the benefit of multiple ozone observations from GEMS geostationary satellite, low Earth orbit (LEO) satellite, and surface networks on summertime ozone simulations through individual or joint data assimilation, built on our previous Observing System Simulation Experiment (OSSE) framework (Shu et al., 2022). We find that data assimilation better represents the exceedance, spatial patterns, and diurnal variations of surface ozone, with a regional mean negative bias reduction from 2.1 to 0.2–1.2 ppbv in ozone simulations as well as precision improvements of a root-mean-square error (RMSE) of by 5–69 % in most Asian countries. Furthermore, the joint assimilation of GEMS and surface observations performs the best. GEMS also brings direct added value for better reproducing ozone vertical distributions, especially in the middle to upper troposphere at low latitudes, but may mask the added value of LEO measurements, which are crucial to constrain surface and upper tropospheric ozone simulations when observations from other platforms are inadequate. Our study provides a valuable reference for ozone data assimilation as multisource observations become gradually available in the era of GEO satellites. [ABSTRACT FROM AUTHOR]

Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1-3 (HNP1-3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information. [ABSTRACT FROM AUTHOR]

The epidermal growth factor receptor (EGFR) has been a particular interest for drug development for treatment of non-small-cell lung cancer (NSCLC). The current third-generation EGFR small-molecule inhibitors, especially osimertinib, are at the forefront clinically for treatment of patients with NSCLC. However, a high percentage of these treated patients developed a tertiary cystein-797 to serine-790 (C797S) mutation in the EGFR kinase domain. This C797S mutation is thought to induce resistance to all current irreversible EGFR TKIs. In this Miniperspective, we present key mechanisms of resistance in response to third-generation EGFR TKIs, and emerging reports on novel EGFR TKIs to combat the resistance. Specifically, we analyze the allosteric and ATP-competitive inhibitors in terms of drug discovery, binding mechanism, and their potency and selectivity against EGFR harboring C797S mutations. Lastly, we provide some perspectives on new challenges and future directions in this field. [ABSTRACT FROM AUTHOR]