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Background: In 2013, China released the Air Pollution Prevention and Control Action Plan (Action Plan), which set the roadmap for national air pollution control actions for the period of 2013 to 2017. A decrease in the fine particulate matter with aerodynamic diameter ≤ 2.5μ m (PM 2.5 ) concentration may lead to a substantial benefit for human health. Objective: We aimed to quantify the relative contributions four factors: emission reductions, changed meteorology, population growth, and a change in baseline mortality rates to the reducedPM 2.5 -related mortality (PM 2.5 -mortality) during the 2013–2017 period and evaluate the importance of emission controls for human health protection in China. Methods: The integrated exposure–response function was adopted to estimate the chronic health effects ofPM 2.5 . The annualPM 2.5 concentrations were estimated from chemical transport model simulations combined with surface observations for 2013 and 2017. Relative contributions toPM 2.5 -mortality from emission reductions and the three factors were individually quantified through scenario analysis. Results: The estimated totalPM 2.5 -mortality in China was 1.389 million [95% confidence interval (CI): 1.005 million, 1.631 million] in 2013 but was substantially reduced to 1.102 million (95% CI: 0.755 million, 1.337 million) in 2017. Emission controls contributed 88.7% to this reduction inPM 2.5 -mortality, while changed meteorology, the change in baseline mortality rates, and population growth during 2013–2017 contributed 9.6, 3.8, and − 2.2 % , respectively. Conclusions: The implementation of the Action Plan has significantly reduced thePM 2.5 concentration in regions of China where population density is high, dominating the decline inPM 2.5 -mortality during 2013–2017. However, the health burden ofPM 2.5 pollution in China is still extremely high compared with that in other developed countries. An aggressive air pollution control strategy should be implemented in densely populated areas to further reduce the health burden.

ATP-sensitive potassium channels (K ATP ) are metabolic sensors that convert the intracellular ATP/ADP ratio to the excitability of cells. They are involved in many physiological processes and implicated in several human diseases. Here we present the cryo-EM structures of the pancreatic K ATP channel in both the closed state and the pre-open state, resolved in the same sample. We observe the binding of nucleotides at the inhibitory sites of the Kir6.2 channel in the closed but not in the pre-open state. Structural comparisons reveal the mechanism for ATP inhibition and Mg-ADP activation, two fundamental properties of K ATP channels. Moreover, the structures also uncover the activation mechanism of diazoxide-type K ATP openers. K ATP channels are energy sensors. Here, authors report the Cryo-EM structures of pancreatic K ATP in both the closed state and the pre-open state. These structures illuminate the mechanism of K ATP channel regulation by the intracellular nucleotides.

Nonenzymatic template-directed RNA copying using chemically activated nucleotides is thought to have played a key role in the emergence of genetic information on the early Earth. A longstanding question concerns the number and nature of different environments that might have been necessary to enable all of the steps from nucleotide synthesis to RNA copying. Here we explore three sequential steps from this overall pathway: nucleotide activation, synthesis of imidazolium-bridged dinucleotides, and template-directed RNA copying. We find that all three steps can take place in one reaction mixture undergoing multiple freeze-thaw cycles. Recent experiments have demonstrated a potentially prebiotic methyl isocyanide-based nucleotide activation chemistry. However, the original version of this approach is incompatible with nonenzymatic RNA copying because the high required concentration of the imidazole activating group prevents the accumulation of the essential imidazolium-bridged dinucleotide. Here we report that ice eutectic phase conditions facilitate not only the methyl isocyanide-based activation of ribonucleotide 5′-monophosphates with stoichiometric 2-aminoimidazole, but also the subsequent conversion of these activated mononucleotides into imidazolium-bridged dinucleotides. Furthermore, this one-pot approach is compatible with template-directed RNA copying in the same reaction mixture. Our results suggest that the simple and common environmental fluctuation of freeze-thaw cycles could have played an important role in prebiotic nucleotide activation and nonenzymatic RNA copying.

ATP-sensitive potassium channels (K ATP ), composed of Kir6 and SUR subunits, convert the metabolic status of the cell into electrical signals. Pharmacological activation of SUR2- containing K ATP channels by class of small molecule drugs known as K ATP openers leads to hyperpolarization of excitable cells and to vasodilation. Thus, K ATP openers could be used to treat cardiovascular diseases. However, where these vasodilators bind to K ATP and how they activate the channel remains elusive. Here, we present cryo-EM structures of SUR2A and SUR2B subunits in complex with Mg-nucleotides and P1075 or levcromakalim, two chemically distinct K ATP openers that are specific to SUR2. Both P1075 and levcromakalim bind to a common site in the transmembrane domain (TMD) of the SUR2 subunit, which is between TMD1 and TMD2 and is embraced by TM10, TM11, TM12, TM14, and TM17. These K ATP openers synergize with Mg-nucleotides to stabilize SUR2 in the NBD-dimerized occluded state to activate the channel. SUR2-containing KATP channels are drug targets for certain vasodilators. Here, the authors determine high-resolution cryo-EM structures of SUR2 in complex with two vasodilators, P1075 and levcromakalim, uncovering the mechanisms of these drugs.

Exposure to elevated surface ozone is damaging to crops. In this study, we performed an analysis of temporal and spatial distributions of relative yield losses (RYLs) attributable to surface ozone for major crops in China from 2010 to 2017, by applying AOT40 metrics (hourly ozone concentration over a threshold of 40 ppbv during the growing season) simulated using a chemical transport model. The major crops in China include wheat, rice (including double early and late rice, and single rice), maize (including north and south maize), and soybean. The aggregated production and associated economic losses in China and major provinces were evaluated by combing annual crop production yields and crop market prices. We estimated that the national annual average AOT40 in China increased from 21.98 ppm h in 2010 to 23.85 ppm h in 2017, with a peak value of 35.69 ppm h in 2014, as simulated with the model. There is significant spatial heterogeneity for the AOT40 and RYLs across the four crops due to the seasonal ozone variations. We calculated that national mean RYLs for wheat, rice, maize, and soybean were 11.45 %–19.74 %, 7.59 %–9.29 %, 0.07 %–3.35 %, and 6.51 %–9.92 %, respectively, from 2010 to 2017. The associated crop yield losses were estimated at 13.81–36.51, 16.89–20.03, 4.59–8.17, and 1.09–1.84 million metric tons (Mt) respectively, which accounted for annual average economic loss of USD 9.55 billion, USD 8.53 billion, USD 2.23 billion, and USD 1.16 billion individually over the 8 years. Our study provides the first long-term quantitative estimation of crop yield losses and their economic cost from surface ozone exposure in China before and after the China Clean Air Act in 2013, and improves understanding of the spatial sensitivity of Chinese crops to ozone impacts.

K ATP channels are metabolic sensors for intracellular ATP/ADP ratios, play essential roles in many physiological processes, and are implicated in a spectrum of pathological conditions. SUR2A-containing K ATP channels differ from other subtypes in their sensitivity to Mg-ADP activation. However, the underlying structural mechanism remains poorly understood. Here we present a series of cryo-EM structures of SUR2A in the presence of different combinations of Mg-nucleotides and the allosteric inhibitor repaglinide. These structures uncover regulatory helix (R helix) on the NBD1-TMD2 linker, which wedges between NBD1 and NBD2. R helix stabilizes SUR2A in the NBD-separated conformation to inhibit channel activation. The competitive binding of Mg-ADP with Mg-ATP to NBD2 mobilizes the R helix to relieve such inhibition, allowing channel activation. The structures of SUR2B in similar conditions suggest that the C-terminal 42 residues of SUR2B enhance the structural dynamics of NBD2 and facilitate the dissociation of the R helix and the binding of Mg-ADP to NBD2, promoting NBD dimerization and subsequent channel activation. Cardiac KATP channels consisting of SUR2A are poorly activated by Mg-ADP compared to other subtypes. Here, the authors present structures of SUR2A and SUR2B, uncovering a regulatory helix that inhibits SUR2A activation.

We compare Community Multiscale Air Quality (CMAQ) model predictions with measured nitrous acid (HONO) concentrations in Beijing, China, for December 2015. The model with the existing HONO chemistry in CMAQ severely underestimates the observed HONO concentrations with a normalized mean bias of −97 %. We revise the HONO chemistry in the model by implementing six additional heterogeneous reactions in the model: the reaction of nitrogen dioxide (NO2) on ground surfaces, the reaction of NO2 on aerosol surfaces, the reaction of NO2 on soot surfaces, the photolysis of aerosol nitrate, the nitric acid displacement reaction, and the hydrochloric acid displacement reaction. The model with the revised chemistry substantially increases HONO predictions and improves the comparison with observed data with a normalized mean bias of −5 %. The photolysis of HONO enhances daytime hydroxyl radical by almost a factor of 2. The enhanced hydroxyl radical concentrations compare favorably with observed data and produce additional sulfate via the reaction with sulfur dioxide, aerosol nitrate via the reaction with nitrogen dioxide, and secondary organic aerosols via the reactions with volatile organic compounds. The additional sulfate stemming from revised HONO chemistry improves the comparison with observed concentration; however, it does not close the gap between model prediction and the observation during polluted days.

ATP-sensitive potassium channels (K ATP) are energy sensors on the plasma membrane. By sensing the intracellular ADP/ATP ratio of β-cells, pancreatic K ATP channels control insulin release and regulate metabolism at the whole body level. They are implicated in many metabolic disorders and diseases and are therefore important drug targets. Here, we present three structures of pancreatic K ATP channels solved by cryoelectron microscopy (cryo-EM), at resolutions ranging from 4.1 to 4.5 Å. These structures depict the binding site of the antidiabetic drug glibenclamide, indicate how Kir6.2 (inward-rectifying potassium channel 6.2) N-terminus participates in the coupling between the peripheral SUR1 (sulfonylurea receptor 1) subunit and the central Kir6.2 channel, reveal the binding mode of activating nucleotides, and suggest the mechanism of how Mg-ADP binding on nucleotide binding domains (NBDs) drives a conformational change of the SUR1 subunit.

BTR1 (SLC4A11) is a NH 3 stimulated H + (OH - ) transporter belonging to the SLC4 family. Dysfunction of BTR1 leads to diseases such as congenital hereditary endothelial dystrophy (CHED) and Fuchs endothelial corneal dystrophy (FECD). However, the mechanistic basis of BTR1 activation by alkaline pH, transport activity regulation and pathogenic mutations remains elusive. Here, we present cryo-EM structures of human BTR1 in the outward-facing state in complex with its activating ligands PIP 2 and the inward-facing state with the pathogenic R125H mutation. We reveal that PIP 2 binds at the interface between the transmembrane domain and the N-terminal cytosolic domain of BTR1. Disruption of either the PIP 2 binding site or protonation of PIP 2 phosphate groups by acidic pH can transform BTR1 into an inward-facing conformation. Our results provide insights into the mechanisms of how the transport activity and conformation changes of BTR1 are regulated by PIP 2 binding and interaction of TMD and NTD. BTR1 is an electrogenic H+ transporter belonging to the bicarbonate transporter family. Here, the authors present structures of BTR1 in different conformations and uncover PIP2 as the activator of BTR1.

The CUL3-RING E3 ubiquitin ligases (CRL3s) play an essential role in response to extracellular nutrition and stress stimuli. The ubiquitin ligase function of CRL3s is activated through dimerization. However, how and why such a dimeric assembly is required for its ligase activity remains elusive. Here, we report the cryo-EM structure of the dimeric CRL3 KLHL22 complex and reveal a conserved N-terminal motif in CUL3 that contributes to the dimerization assembly and the E3 ligase activity of CRL3 KLHL22 . We show that deletion of the CUL3 N-terminal motif impairs dimeric assembly and the E3 ligase activity of both CRL3 KLHL22 and several other CRL3s. In addition, we found that the dynamics of dimeric assembly of CRL3 KLHL22 generates a variable ubiquitination zone, potentially facilitating substrate recognition and ubiquitination. These findings demonstrate that a CUL3 N-terminal motif participates in the assembly process and provide insights into the assembly and activation of CRL3s. The assembly integrity of dimeric CRL3 E3 ligases are important in various physiological and pathological processes. Here, the authors show that an evolutionarily conserved CUL3 N-terminal motif contributes to both the assembly and activity of dimeric CRL3 E3 ligases.