Vertical Evolution of Ozone Formation Sensitivity Based on Synchronous Vertical Observations of Ozone and Proxies for Its Precursors: Implications for Ozone Pollution Prevention Strategies.

Photochemical ozone (O3) formation in the atmospheric boundary layer occurs at both the surface and elevated altitudes. Therefore, the O3 formation sensitivity is needed to be evaluated at different altitudes before formulating an effective O3 pollution prevention and control strategy. Herein, we explore the vertical evolution of O3 formation sensitivity via synchronous observations of the vertical profiles of O3 and proxies for its precursors, formaldehyde (HCHO) and nitrogen dioxide (NO2), using multi-axis differential optical absorption spectroscopy (MAX-DOAS) in urban areas of the Beijing-Tianjin-Hebei (BTH), Yangtze River Delta (YRD), and Pearl River Delta (PRD) regions in China. The sensitivity thresholds indicated by the HCHO/NO2 ratio (FNR) varied with altitude. The VOC-limited regime dominated at the ground level, whereas the contribution of the NOx-limited regime increased with altitude, particularly on heavily polluted days. The NOx-limited and transition regimes played more important roles throughout the entire boundary layer than at the surface. The feasibility of extreme NOx reduction to mitigate the extent of the O3 pollution was evaluated using the FNR-O3 curve. Based on the surface sensitivity, the critical NOx reduction percentage for the transition from a VOC-limited to a NOx-limited regime is 45-72%, which will decrease to 27-61% when vertical evolution is considered. With the combined effects of clean air action and carbon neutrality, O3 pollution in the YRD and PRD regions will transition to the NOx-limited regime before 2030 and be mitigated with further NOx reduction.

Quantum control of field-free molecular orientation.

Generating field-free (non-stationary) orientation of molecules in space has been a longstanding goal in the field of quantum control of molecular rotation, which has significant applications in physical chemistry, chemical physics, strong-field physics, and quantum information science. In this Perspective, we review and examine several representative control schemes developed in recent years and implemented in theoretical and experimental areas for generating field-free orientation of molecules. By conducting numerical simulations of different control schemes on the same molecular system, we demonstrate that quantum coherent control, specifically targeting a limited number of the lowest-lying rotational levels to achieve an optimal superposition, can result in a high degree of orientation. To this end, we provide an overview of our latest developed analytical method, which enables the precise design of terahertz field parameters through resonant excitation. This design approach facilitates the attainment of desired field-free orientations by optimizing the amplitudes and phases of rotational wave functions for the selected rotational levels. Finally, we outlook the significance of such progress in multiple frontier research fields, highlighting its potential applications in ultracold physics, quantum computation, quantum simulation, and quantum metrology.

Tobacco excise tax reform: From the perspective of "tax to control tobacco" policy in China.

The consumption of tobacco is harmful to health and has huge social costs. "Tax to control tobacco" is a widely implemented tobacco control measure all over the world. In order to examine the achievements of two tobacco excise tax reforms in China in 2009 and 2015 on controlling tobacco consumption, we first establish an intertemporal consumption model for addictive goods, and then validate the effectiveness of the two tobacco excise tax reforms using a Continuous Difference-in-Differences Model based on the panel data from 294 cities in China from 2007 to 2018. The results show that the tobacco excise tax reform in 2015 considerably reduced tobacco consumption, while the reform in 2009 did not, providing empirical evidence on the importance of "price links to tax" for tobacco control. Additionally, the study discovers that the tax reform has a heterogeneous effect on the age of smokers, the price of cigarettes, and city size.

Synthesis and biological evaluation of 7H-pyrrolo [2,3-d] pyrimidine derivatives as potential p21-activated kinase 4 (PAK4) inhibitors.

PAK4 has been validated as a crucial effector of various signal pathways and play an important role in driving tumor progression. Here, we developed a series of 7H-pyrrolo [2,3-d] pyrimidine derivatives as PAK4 inhibitors. Compounds 5n and 5o showed higher enzymatic inhibitory activities (IC50 = 2.7 and 20.2 nM, respectively) and potent activity (IC50 = 7.8 and 38.3 nM, respectively) against MV4-11 cell line. Further flow cytometry assay revealed that the compound 5n can arrest MV4-11 cells at G0/G1 phase and induce cell apoptosis. Molecular mechanism study indicated that compound 5n regulated the phosphorylation of PAK4 in vitro. The docking study supported that compound 5n binds to PAK4 through various hydrogen bonding interactions and hydrophobic interactions. Thus, compound 5n represents a promising lead for the discovery of PAK4 directed therapeutic agents and may be considered for further drug development.

Vertical distributions and potential sources of wintertime atmospheric pollutants and the corresponding ozone production on the coast of Bohai Sea.

This study investigated the wintertime vertical distributions and source areas of aerosols, NO2, and HCHO in a coastal city of Dongying from December 2020 to March 2021, using ground-based multi-axis differential optical absorption spectroscopy (MAX-DOAS) and a potential source contribution function (PSCF) model, respectively. Moreover, the chemical production sensitivity of O3 at different height layers was analyzed using HCHO/NO2 ratios. The results revealed that the wintertime averaged highest concentrations of aerosol (1.25 km-1), NO2 (14.81 ppb), and HCHO (2.32 ppb) were mainly distributed at the surface layer, 100-200 m layer, and 200-300 m layer, respectively. Regarding the diurnal cycles, high concentrations of aerosol (>1.4 km-1) and NO2 (>16.0 ppb) usually appeared in the early morning and late afternoon, while high concentrations of HCHO (>2.5 ppb) usually occurred during 12:00-15:00. The PSCF model revealed that the wintertime aerosol mainly originated from Shandong, northern Jiangsu, Korea, and the northwestern Mongolian Plateau. Below 200 m, NO2 was mainly from western Shandong, whereas above 600 m, it was mainly from northern Shandong and the Beijing-Tianjin-Hebei (BTH) region. The corresponding sources for HCHO were central and southern Shandong (below 200 m) and northern Shandong, northern Jiangsu, and southeastern BTH (above 600 m). In addition, the chemical production sensitivity of O3 below 100 m was observed only in the VOC-limited regime. The percentages of O3 production under the NOx-limited, NOx-VOC-limited, and VOC-limited regimes were 10.75% (31.18%), 4.30% (19.35%), and 84.95% (49.47%) at the 500-600 m (900-1000 m) layer. This study has guiding significance for the coordinated control of PM2.5 and O3, and can assist in the implementation of regional joint prevention and control strategies for air pollutants.

Vertical distribution and temporal evolution of formaldehyde and glyoxal derived from MAX-DOAS observations: The indicative role of VOC sources.

Formaldehyde (HCHO) and glyoxal (CHOCHO) are important oxidization intermediates of most volatile organic compounds (VOCs), but their vertical evolution in urban areas is not well understood. Vertical profiles of HCHO, CHOCHO, and nitrogen dioxide (NO2) were retrieved from ground-based Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) observations in Hefei, China. HCHO and CHOCHO vertical profiles prefer to occur at higher altitudes compared to NO2, which might be caused by the photochemistry-oxidation of longer-lived VOCs at higher altitudes. Monthly means of HCHO concentrations were higher in summer, while enhanced amounts of NO2 were mainly observed in winter. CHOCHO exhibited a hump-like seasonal variation, with higher monthly-averaged values not only occurred in warm months (July-August) but also in cold months (November-December). Peak values mainly occurred during noon for HCHO but emerged in the morning for CHOCHO and NO2, suggesting that HCHO is stronger link to photochemistry than CHOCHO. We further use the glyoxal to formaldehyde ratio (GFR) to investigate the VOC sources at different altitudes. The lowest GFR value is almost found in the altitude from 0.2 to 0.4 km, and then rises rapidly as the altitude increases. The GFR results indicate that the largest contributor of the precursor VOC is biogenic VOCs at lower altitudes, while at higher altitudes is anthropogenic VOCs. Our findings provide a lot more insight into VOC sources at vertical direction, but more verification is recommended to be done in the future.

Novel Promotion of Sulfuration for Hg0 Conversion over V2O5-MoO3/TiO2 with HCl at Low Temperatures: Hg0 Adsorption, Hg0 Oxidation, and Hg2+ Adsorption.

In this work, the commercial selective catalytic reduction (SCR) catalyst V2O5-MoO3/TiO2 was sulfureted with H2S to improve both its capability for elemental mercury (Hg0) removal at low temperatures and its resistance to SO2 and H2O. Hg0 removal over both V2O5-MoO3/TiO2 and sulfureted V2O5-MoO3/TiO2 involved the catalytic oxidation of Hg0 to HgCl2 and the chemical adsorption of gaseous Hg0; therefore, the effect of sulfuration on Hg0 chemical adsorption and the catalytic oxidation of Hg0 to HgCl2 over V2O5-MoO3/TiO2 and its resistance to SO2 and H2O were investigated using Hg balance analysis. Kinetic analysis showed that the rates of the chemical adsorption and oxidation of Hg0 were both in direct proportion to the concentration of physically adsorbed Hg0. The physical adsorption of gaseous Hg0 on V2O5-MoO3/TiO2 was remarkably promoted after sulfuration, and the physical adsorption of gaseous Hg0 over sulfureted V2O5-MoO3/TiO2 was scarcely inhibited by SO2 and H2O. Therefore, the performance of V2O5-MoO3/TiO2 for Hg0 removal and its resistance to SO2 and H2O were both improved after sulfuration. Even more remarkably, sulfureted V2O5-MoO3/TiO2 can adsorb gaseous HgCl2, which resulted from Hg0 oxidation. Therefore, sulfureted V2O5-MoO3/TiO2 showed an excellent performance to recover Hg0 from coal-fired power plants, which can then be converted to liquid Hg.

Different Design Strategies for Metal Sulfide Sorbents to Capture Low Concentrations of Gaseous Hg0 in Coal-Fired Flue Gas and High Concentrations of Gaseous Hg0 in Smelting Flue Gas.

Capturing gaseous Hg0 using regenerable metal sulfides is a promising technology to recover gaseous Hg0 from both coal-fired flue gas (CFG) and smelting flue gas (SFG) for the centralized control. Gaseous Hg0 concentration in SFG is 2-3 orders of magnitude higher than that in CFG; therefore, the design strategy of metal sulfides for capturing gaseous Hg0 from CFG is quite different from that from SGF. In this work, the structure-activity relationship of metal sulfides to capture Hg0 was investigated according to the remarkable difference in MoO3 loading on sulfureted FeTiOx to capture low/high concentrations of gaseous Hg0. The rate of Hg0 adsorption onto metal sulfides was mainly related to the amounts of adsorption sites and S22- on the surface, the affinity of adsorption sites to gaseous Hg0, and the gaseous Hg0 concentration. Meanwhile, the capacity for Hg0 adsorption was approximately equal to the less of the amount of adsorption sites and S22- on the surface. Furthermore, capturing low concentrations of gaseous Hg0 from CFG required the metal sulfide sorbents having more adsorption sites with strong affinity to gaseous Hg0, while capturing high concentrations of gaseous Hg0 from SFG required the sorbents with enough adsorption sites.

Characteristic analysis of continuous new particle formation events in Hefei: A case study of the May Day holiday in China.

Studying the characteristics of new particle formation (NPF) is conducive to exploring the impact of atmospheric particulate matter on the climate, environment, and human health. The particle number size distributions (5.6-560 nm) of aerosols were measured using a fast mobility particle sizer (FMPS) from 1 to 11 May 2019. The clean atmosphere was one of the basic conditions for the occurrence of this continuous new particle formation events. It started between 9:00 and 12:00, and it mainly ended after 20:00. The growth rate (GR) and condensation sink (CS) values in Hefei were 2.98 ± 0.97 nm·h-1 and (3.0 ± 0.4) × 10-2 s-1, respectively. Back trajectory clustering analysis revealed that the mass concentration of the air masses from the southeastern part of Henan Province and the southern part of Anhui Province surrounding the study area were relatively high. The analysis results of the potential source contribution function (PSCF) and the concentration weighted trajectory (CWT) methods show that in addition to local pollution, the long-distance transport of pollutants in the Yangtze River Delta (YRD) greatly contributed to the accumulation modal particulate concentration in Hefei. Moreover, the population affected by PM2.5 during the observation period reached 8.19 × 104, accounting for 1.08% to the total population in Hefei. The premature death cases associated with PM2.5 reached 8.35 × 102. This study is helpful to understand the main influencing factors of consecutive NPF events and the health risks of fine particles.

Vertical distributions of tropospheric SO2 based on MAX-DOAS observations: Investigating the impacts of regional transport at different heights in the boundary layer.

Information on the vertical distribution of air pollutants is essential for understanding their spatiotemporal evolution underlying urban atmospheric environment. This paper presents the SO2 profiles based on ground-based Multi-Axis Differential Optical Absorption Spectroscopy (MAX-DOAS) measurements from March 2018 to February 2019 in Hefei, East China. SO2 decrease rapidly with increasing heights in the warm season, while lifted layers were observed in the cold season, indicating accumulation or long-range transport of SO2 in different seasons might occur at different heights. The diurnal variations of SO2 were roughly consistent for all four seasons, exhibiting the minimum at noon and higher values in the morning and late afternoon. Lifted layers of SO2 were observed in the morning for fall and winter, implying the accumulation or transport of SO2 in the morning mainly occurred at the top of the boundary layer. The bivariate polar plots showed that weighted SO2 concentrations in the lower altitude were weakly dependent on wind, but in the middle and upper altitudes, higher weighted SO2 concentrations were observed under conditions of middle-high wind speed. Concentration weighted trajectory (CWT) analysis suggested that potential sources of SO2 in spring and summer were local and transported mainly occurred in the lower altitude from southern and eastern areas; while in fall and winter, SO2 concentrations were deeply affected by long-range transport from northwestern and northern polluted regions in the middle and upper altitudes. Our findings provide new insight into the impacts of regional transport at different heights in the boundary layer on SO2 pollution.

Different roles of FeS and FeS2 on magnetic FeSx for the selective adsorption of Hg2+ from waste acids in smelters: Reaction mechanism, kinetics, and structure-activity relationship.

Magnetic FeSx was developed as a high-performance sorbent for selectively adsorbing Hg2+ from waste acids in smelters. However, further improvement of its ability for Hg2+ adsorption was extremely restricted due to the lack of reaction mechanisms and structure-activity relationships. In this study, the roles of FeS and FeS2 on magnetic FeSx for Hg2+ adsorption were investigated with alternate adsorption of Hg2+ without/with Cl-. The structure-activity relationship of magnetic FeSx for Hg2+ adsorption and the negative effect of acid erosion were elucidated using kinetic analysis. FeS can react with Hg2+ with 1:1 stoichiometric ratio to form HgS, while FeS2 can react with Hg2+ in the presence of Cl- with novel 1:3 stoichiometric ratio to form Hg3S2Cl2. The rate of magnetic FeSx for Hg2+ adsorption was related to the instantaneous amounts of FeS and threefold FeS2 on magnetic FeSx and the amount of Hg2+ adsorbed. Meanwhile, its capacity for Hg2+ adsorption was related to the initial sum of FeS amount and threefold FeS2 amount on the surface and their ratios by acid erosion. Then, magnetic FeSx-400 was devised with adsorption rate of 2.12 mg g-1 min-1 and capacity of 1092 mg g-1 to recover Hg2+ from waste acids for centralized control.

Investigating vertical distributions and photochemical indications of formaldehyde, glyoxal, and NO2 from MAX-DOAS observations in four typical cities of China.

Formaldehyde (HCHO), glyoxal (CHOCHO), and nitrogen dioxide (NO2) are crucial in atmospheric photochemical processes at both surface and elevated altitudes. This study presents synchronous multi-axis differential optical absorption spectroscopy (MAX-DOAS) measurements of the vertical distributions of summertime HCHO, CHOCHO and NO2 in four representative megacities within the Beijing-Tianjin-Hebei (BTH), Yangtze River Delta (YRD), Sichuan Basin (SB), and Pearl River Delta (PRD) regions of China. The vertical distributions of HCHO and CHOCHO tended to occur at higher altitudes compared to NO2, influenced by both primary emissions near the ground and photochemical oxidation processes at elevated altitudes. Source separation regression analysis using the CO-CHOCHO trace pair identified secondary formation as the predominant source of ambient HCHO. In urban areas, the ratio of CHOCHO to secondary HCHO (RGFsec) serves as a more reliable metric at ground level for diagnosing VOC precursor sources, excluding the interference of primary and background HCHO. The increase in RGF values at higher altitudes highlights the relative contribution of VOCs favoring CHOCHO production. Moreover, four indicators (e.g. FNR, FNRsec, GNR, and MNR) were utilized to characterize O3 formation sensitivity at different altitudes. The range of FNR, FNRsec, GNR, and MNR marking the O3 formation sensitivity regime varies regionally, highlighting the need for localized assessments. The VOC-limited regime dominated at the ground level, whereas the contribution of the NOx-limited regime increased with altitude. Therefore, a comprehensive control strategy addressing both VOC and NOx emissions across different altitudes is essential for effectively mitigating photochemical pollution in urban areas of China.

Sleep Promotion by 3-Hydroxy-4-Iminobutyric Acid in Walnut Diaphragma juglandis Fructus.

Insufficient sleep can produce a multitude of deleterious repercussions on various domains of human well-being. Concomitantly, the walnut (Juglans mandshurica) confers numerous salutary biological activities pertaining to sleep. Nevertheless, the sedative and hypnotic capacities of walnut's functional constituents remain obscure. In this investigation, we analyzed the sedative and hypnotic components of the walnut Diaphragma juglandis fructus and innovatively discovered a compound, defined as 3-hydroxy-4-iminobutyric acid (HIBA), which disrupts motor activity and enhances sleep duration by regulating the neurotransmitters (GABA, DA, etc.) within the brain and serum of mice. Subsequently, a metabolomics approach of the serum, basal ganglia, hypothalamus, and hippocampus as well as the gut microbiota was undertaken to unravel the underlying molecular mechanisms of sleep promotion. Our data reveal that HIBA can regulate the metabolism of basal ganglia (sphingolipids, acylcarnitines, etc.), possibly in relation to HIBA's influence on the gut microbiome (Muribaculum, Bacteroides, Lactobacillus, etc.). Therefore, we introduce a novel natural product, HIBA, and explicate the modulation of sleep promotion in mice based on the microbiota-gut-brain axis. This study contributes fresh insights toward natural product-based sleep research.

Selective removal of Hg2+ from acidic wastewaters using sulfureted Fe2TiO5: Underlying mechanism and its application as a regenerable sorbent for recovering Hg from waste acids of smelters.

The selective removal of Hg2+ from waste acids containing high concentrations of other metal cations, such as Cu2+, Zn2+, and Cd2+, which are discharged from nonferrous metal smelting industries, is in great demand. Herein, sulfureted Fe2TiO5 was developed as a regenerable magnetic sorbent to recover Hg2+ from waste acids for centralized control. Sulfureted Fe2TiO5 exhibited an excellent ability for Hg2+ removal with the capacity of 292-317 mg g-1 and the rate of 49.5-57.6 mg g-1 h-1 at pH=2-4. Meanwhile, it exhibited an excellent selectivity for Hg2+ removal that not only the coexisting Cu2+, Zn2+, and Cd2+ can scarcely be adsorbed but also Hg2+ adsorption was hardly inhibited. The mechanism and kinetic studies indicated that the Fe2+ in the FeS2 coated on sulfureted Fe2TiO5 was exchanged with Hg2+ adsorbed at a Fe2+ to Hg2+ mole ratio of 1:2. Meanwhile, most of the Hg2+ removed by sulfureted Fe2TiO5 can be thermally desorbed primarily as ultra-high concentrations of gaseous Hg0, which can finally be recovered as liquid Hg0 for centralized control in combination with existing Hg0-recovery devices in smelters. Moreover, the spent sulfureted Fe2TiO5 could be regenerated for duty-cycle operations with re-sulfuration without a remarkable degradation of the Hg2+-removal performance. Therefore, Hg2+ recovery using sulfureted Fe2TiO5 may be a promising, low-cost, and environmentally friendly technology for the centralized control of Hg2+ in waste acids discharged from smelters.

Outstanding performance of sulfurated titanomaghemite (Fe2TiO5) for hexavalent chromium removal: Sulfuration promotion mechanism and its application in chromium resource recovery.

A lot of magnetic sorbents have been developed to meet the current demand for removing Cr (VI) from wastewater. However, the application of magnetic sorbents remains restricted by the unsatisfactory Cr (VI) removal efficiency, sorbent regeneration, and safe disposition of adsorbed Cr species. In this study, magnetic titanomaghemite (Fe2TiO5) was sulfurated with gaseous H2S to improve its Cr (VI) removal efficiency. Sulfuration significantly improved the Cr (VI) removal efficiency of Fe2TiO5 from 3%-14% to 27%-82% at pH 4-10 due to drastically increased the electrostatic adsorption of Cr (VI) and heterogeneous reduction of adsorbed Cr (VI) to Cr (III). Furthermore, the sulfurated Fe2TiO5 recovered using magnetic separation can be regenerated by re-sulfuration without degrading the Cr (VI) removal efficiency, therefore, sulfurated Fe2TiO5 can be recycled for Cr (VI) removal after the regeneration. Moreover, Cr (VI) in aqueous solution can be enriched on sulfurated Fe2TiO5 after multiple adsorptions in the form of Cr2O3 in a content of more than 30% what can be considered as a source of chrome ore. Therefore, sulfurated Fe2TiO5 may be a promising, low-cost, and environment-friendly sorbent for Cr recovery as a co-benefit of Cr (VI) removal from wastewater.

Comparison of pyrite-phase transition metal sulfides for capturing leaked high concentrations of gaseous elemental mercury in indoor air: Mechanism and adsorption/desorption kinetics.

Understanding the characteristics of pyrite-phase transition metal sulfides for the adsorption and desorption of gaseous elemental mercury (Hg0) is of vital significance for their applications in gaseous Hg0 capture. In this study, the adsorption and desorption of gaseous Hg0 onto pyrite-phase transition metal sulfides (i.e., FeS2/TiO2, CoS2/TiO2, and NiS2/TiO2) were compared, and the mechanisms of their differences were revealed by the kinetic analysis. The Co/NiS and SS bonds in dumbbell-shaped CoS2 and NiS2 were not entirely broken after oxidizing physically adsorbed Hg0, whereas the FeS and SS bonds in dumbbell-shaped FeS2 were. Thus, the activation energies of CoS2/TiO2 and NiS2/TiO2 for oxidizing physically adsorbed Hg0 were smaller than that of FeS2/TiO2, causing the stronger abilities of CoS2/TiO2 and NiS2/TiO2 to oxidize physically adsorbed Hg0 than that of FeS2/TiO2. However, the bonding strengths of Hg-S in HgS adsorbed on dumbbell-shaped CoS2 and NiS2 were relatively weaker because of the sharing of S2- in HgS with S- and Co2+/Ni2+, causing the decreases in heat stabilities of HgS adsorbed on CoS2/TiO2 and NiS2/TiO2. Therefore, HgS adsorbed on CoS2/TiO2 and NiS2/TiO2 can be voluntarily decomposed to release gaseous Hg0, which should be combined with FeS2/TiO2 for the emergency treatment of liquid Hg0 leakage indoors.

Inferring vertical variability and diurnal evolution of O3 formation sensitivity based on the vertical distribution of summertime HCHO and NO2 in Guangzhou, China.

The vertical distributions of formaldehyde (HCHO) and nitrogen dioxide (NO2) and their indicative roles in ozone (O3) sensitivity are important for designing O3 mitigation strategies. Using hyperspectral remote sensing observations, tropospheric vertical profiles of HCHO, NO2, and aerosol extinction were investigated in Guangzhou, China from July to September 2019. On both O3 non-exceedance and polluted days, the HCHO and aerosol vertical profiles exhibited similar Gaussian shapes, but the NO2 profile exhibited an exponential decreasing shape. HCHO and aerosol were especially sensitive to O3 pollution, with higher values generally occurring at approximately noon and late afternoon at higher altitudes. We attempted to study the diurnal evolution of O3 sensitivity at different altitudes based on the HCHO to NO2 ratio (FNR) vertical profile. The FNR thresholds marking the transition regime (2.5 < FNR < 4.0) were derived from the relationship between the increase in O3 (∆O3) and FNR. Our results showed that O3 sensitivity tends to be VOC-limited both at lower (below approximately 0.4 km) and higher (above approximately 1.8 km) altitudes throughout the daytime. In the middle altitudes, the photochemical formation of O3 was mainly in the transition/NOx-limited regime in the morning and afternoon but in the VOC-limited regime at noontime. The relationship between TROPOMI column FNR and near-surface O3 sensitivity was further investigated. Compared with the MAX-DOAS near-surface FNR, slightly higher values of column FNR would increase the number of days classified as transition regimes, which was mainly caused by the inhomogeneous vertical distribution of HCHO and NO2 in the lower troposphere. This study provides an improved understanding of vertical variability and diurnal evolution of O3 formation sensitivity.

Design and synthesis of HDAC inhibitors to enhance the therapeutic effect of diffuse large B-cell lymphoma by improving metabolic stability and pharmacokinetic characteristics.

Histone deacetylases (HDAC) are clinically validated and attractive epigenetic drug targets for human cancers. Several HDAC inhibitors have been approved for cancer treatment to date, however, clinical applications have been limited due to the poor pharmacokinetics, bioavailability, selectivity of the HDAC inhibitors and most of them need to be combined with other drugs to achieve better results. Here, we describe our efforts toward the discovery of a novel series of lactam-based derivatives as selective HDAC inhibitors. Intensive structural modifications lead to the identification of compound 24g as the most active Class I HDAC Inhibitor, along with satisfactory metabolic stability in vitro (t1/2, human = 797 min) and the desirable oral bioavailability (F = 92%). More importantly, compound 24g showed good antitumor efficacy in a TMD-8 xenograft model (TGI = 77%) without obvious toxicity. These results indicated that Class I HDAC Inhibitor could be potentially used to treat certain diffuse large B-cell lymphoma therapeutics.

Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies.

Cyclin-dependent kinase 9 (CDK9) is a transcriptional regulator and a potential therapeutic target in hematologic malignancies. Selective and transient CDK9 inhibition reduces Mcl-1 expression and induces apoptosis in Mcl-1-dependent tumor cells for survival. Here, we describe our efforts to discover a novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one as CDK9 inhibitors. Compound 32k was identified as a selective CDK9 inhibitor with short pharmacokinetic and physicochemical properties suitable for intravenous administration. Short-term treatment with 32k resulted in a rapid dose-dependent decrease in cellular p-Ser2-RNAPII, Mcl-1 and c-Myc, leading to apoptosis in the MV4-11 cell line. Correspondingly, significant in vivo antitumor efficacy was observed in xenograft models derived from multiple hematological tumors with intermittent 32k dosing. These results provide evidence that selective transient CDK9 inhibitors could be used for the treatment of hematologic malignancies.

Discovery of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as novel and potent bromodomain and extra-terminal (BET) inhibitors with anticancer efficacy.

As epigenetic readers, bromodomain and extra-terminal domain (BET) family proteins bind to acetylated-lysine residues in histones and recruit protein complexes to promote transcription initiation and elongation. Inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for cancer. Herein, we describe our efforts toward the discovery of a novel series of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as BET inhibitors. Intensive structural modifications led to the identification of compound 35f as the most active inhibitor of BET BRD4 with selectivity against BET family proteins. Further biological studies revealed that compound 35f can arrest the cell cycle in G0/G1 phase and induce apoptosis via decreasing the expression of c-Myc and other proteins related to cell cycle and apoptosis. More importantly, compound 35f showed favorable pharmacokinetic properties and antitumor efficacy in MV4-11 mouse xenograft model with acceptable tolerability. These results indicated that BET inhibitors could be potentially used to treat hematologic malignancies and some solid tumors.