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The emergence of aerosol reanalyses in recent years has facilitated a comprehensive and systematic evaluation of aerosol optical depth (AOD) trends and attribution over multi-decadal timescales. Notable multi-year aerosol reanalyses currently available include NAAPS-RA from the US Naval Research Laboratory, the NASA MERRA-2, JRAero from the Japan Meteorological Agency (JMA), and CAMSRA from Copernicus/ECMWF. These aerosol reanalyses are based on differing underlying meteorology models, representations of aerosol processes, as well as data assimilation methods and treatment of AOD observations. This study presents the basic verification characteristics of these four reanalyses versus both AERONET and MODIS retrievals in monthly AOD properties and identifies the strength of each reanalysis and the regions where divergence and challenges are prominent. Regions with high pollution and often mixed fine-mode and coarse-mode aerosol environments, such as South Asia, East Asia, Southeast Asia, and the Maritime Continent, pose significant challenges, as indicated by higher monthly AOD root mean square error. Moreover, regions that are distant from major aerosol source areas, including the polar regions and remote oceans, exhibit large relative differences in speciated AODs and fine-mode versus coarse-mode AODs among the four reanalyses. To ensure consistency across the globe, a multi-reanalysis consensus (MRC, i.e., ensemble mean) approach was developed similarly to the International Cooperative for Aerosol Prediction Multi-Model Ensemble (ICAP-MME). Like the ICAP-MME, while the MRC does not consistently rank first among the reanalyses for individual regions, it performs well by ranking first or second globally in AOD correlation and RMSE, making it a suitable candidate for climate studies that require robust and consistent assessments.

Abstract The computational balance between the model grid resolution and the complexity of the data assimilation technique is essential for accurate aerosol forecasting and obtaining aerosol reanalysis data sets. This study aimed to develop a high‐resolution aerosol assimilation system. A 2‐dimensional variational method (2DVar) was implemented in a non‐hydrostatic icosahedral atmospheric model (NICAM). This new model (NICAM/2DVar), with a global grid size of 56 km, assimilated the observed aerosol optical depth (AOD) that is estimated by combining multiple products of geostationary and polar‐orbital satellites. The model results were evaluated against ground‐based AOD observations on a global scale. They exhibited higher correlations, lower uncertainties, and lower biases than those obtained without the 2DVar. The model also reproduced the observed surface aerosols (PM2.5) mass concentrations, especially in Kyushu, Japan. This occurred because the satellite‐estimated AODs over ocean close to air pollution sources were obtained for many occasions. The correlation coefficient values against the PM2.5 observations increased from 0.44 to 0.65 compared to the results without the 2DVar. The impact of the 2DVar on the forecast results was investigated, and the forecast values for 2–3 days were improved. Because satellite‐retrieved AODs are often lacking over land owing to retrieval difficulties, the use of ground‐based AODs in assimilations is essential for precise processing the of aerosol reanalysis data sets. The computational cost with the use of the 2DVar was only 0.6% more than that without its use. Thus, aerosol assimilation using the NICAM/2DVar can be realistically extended to finer grid sizes.

In this study, we developed a data assimilation (DA) system for chemical transport model (CTM) simulations using an ensemble Kalman filter (EnKF) technique. This DA technique is easy to implement in an existing system without seriously modifying the original CTM and can provide flow-dependent corrections based on error covariance by short-term ensemble propagations. First, the PM2.5 observations at ground stations were assimilated in this DA system every 6 h over South Korea for the period of the KORUS–AQ campaign from 1 May to 12 June 2016. The DA performances with the EnKF were then compared to a control run (CTR) without DA and a run with three-dimensional variational (3D-Var) DA. Consistent improvements owing to the initial conditions (ICs) assimilated with the EnKF were found in the DA experiments at a 6 h interval compared to the CTR run and to the run with 3D-Var. In addition, we attempted to assimilate the ground observations from China to examine the impacts of improved boundary conditions (BCs) on the PM2.5 predictability over South Korea. The contributions of the ICs and BCs to improvements in the PM2.5 predictability were also quantified. For example, the relative reductions in terms of the normalized mean bias (NMB) were found to be approximately 27.2 % for the 6 h reanalysis run. A series of 24 h PM2.5 predictions were additionally conducted each day at 00:00 UTC with the optimized ICs. The relative reduction of the NMB was 17.3 % for the 24 h prediction run when the updated ICs were applied at 00:00 UTC. This means that after the application of the updated BCs, an additional 9.0 % reduction in the NMB was achieved for 24 h PM2.5 predictions in South Korea.

This study provides comparisons of aerosol representation methods incorporated into a regional-scale nonhydrostatic meteorology–chemistry model (NHM-Chem). Three options for aerosol representations are currently available: the five-category non-equilibrium (Aitken, soot-free accumulation, soot-containing accumulation, dust, and sea salt), three-category non-equilibrium (Aitken, accumulation, and coarse), and bulk equilibrium (submicron, dust, and sea salt) methods. The three-category method is widely used in three-dimensional air quality models. The five-category method, the standard method of NHM-Chem, is an extensional development of the three-category method and provides improved predictions of variables relating to aerosol–cloud–radiation interaction processes by implementing separate treatments of light absorber and ice nuclei particles, namely, soot and dust, from the accumulation- and coarse-mode categories (implementation of aerosol feedback processes to NHM-Chem is still ongoing, though). The bulk equilibrium method was developed for operational air quality forecasting with simple aerosol dynamics representations. The total CPU times of the five-category and three-category methods were 91 % and 44 % greater than that of the bulk method, respectively. The bulk equilibrium method was shown to be eligible for operational forecast purposes, namely, the surface mass concentrations of air pollutants such as O3, mineral dust, and PM2.5. The simulated surface concentrations and depositions of bulk chemical species of the three-category method were not significantly different from those of the five-category method. However, the internal mixture assumption of soot/soot-free and dust/sea salt particles in the three-category method resulted in significant differences in the size distribution and hygroscopicity of the particles. The unrealistic dust/sea salt complete mixture of the three-category method induced significant errors in the prediction of the mineral dust-containing cloud condensation nuclei (CCN), which alters heterogeneous ice nucleation in cold rain processes. The overestimation of soot hygroscopicity by the three-category method induced errors in the BC-containing CCN, BC deposition, and light-absorbing aerosol optical thickness (AAOT). Nevertheless, the difference in AAOT was less pronounced with the three-category method because the overestimation of the absorption enhancement was compensated by the overestimation of hygroscopic growth and the consequent loss due to in-cloud scavenging. In terms of total properties, such as aerosol optical thickness (AOT) and CCN, the results of the three-category method were acceptable.

We developed a new aerosol satellite retrieval algorithm combining a numerical aerosol forecast. In the retrieval algorithm, the short-term forecast from an aerosol data assimilation system was used as an a priori estimate instead of spatially and temporally constant values. This method was demonstrated using observation of the Advanced Himawari Imager onboard the Japan Meteorological Agency's geostationary satellite Himawari-8. Overall, the retrieval results incorporated strengths of the observation and the model and complemented their respective weaknesses, showing spatially finer distributions than the model forecast and less noisy distributions than the original algorithm. We validated the new algorithm using ground observation data and found that the aerosol parameters detectable by satellite sensors were retrieved more accurately than an a priori model forecast by adding satellite information. Further, the satellite retrieval accuracy was improved by introducing the model forecast instead of the constant a priori estimates. By using the assimilated forecast for an a priori estimate, information from previous observations can be propagated to future retrievals, leading to better retrieval accuracy. Observational information from the satellite and aerosol transport by the model are incorporated cyclically to effectively estimate the optimum field of aerosol.

We introduce a Multi-mOdel Multi-cOnstituent Chemical data assimilation (MOMO-Chem) framework that directly accounts for model error in transport and chemistry, and we integrate a portfolio of data assimilation analyses obtained using multiple forward chemical transport models in a state-of-the-art ensemble Kalman filter data assimilation system. The data assimilation simultaneously optimizes both concentrations and emissions of multiple species through ingestion of a suite of measurements (ozone, NO2, CO, HNO3) from multiple satellite sensors. In spite of substantial model differences, the observational density and accuracy was sufficient for the assimilation to reduce the multi-model spread by 20 %–85 % for ozone and annual mean bias by 39 %–97 % for ozone in the middle troposphere, while simultaneously reducing the tropospheric NO2 column biases by more than 40 % and the negative biases of surface CO in the Northern Hemisphere by 41 %–94 %. For tropospheric mean OH, the multi-model mean meridional hemispheric gradient was reduced from 1.32±0.03 to 1.19±0.03, while the multi-model spread was reduced by 24 %–58 % over polluted areas. The uncertainty ranges in the a posteriori emissions due to model errors were quantified in 4 %–31 % for NOx and 13 %–35 % for CO regional emissions. Harnessing assimilation increments in both NOx and ozone, we show that the sensitivity of ozone and NO2 surface concentrations to NOx emissions varied by a factor of 2 for end-member models, revealing fundamental differences in the representation of fast chemical and dynamical processes. A systematic investigation of model ozone response and analysis increment in MOMO-Chem could benefit evaluation of future prediction of the chemistry–climate system as a hierarchical emergent constraint.

Acidifying species in precipitation can have severe impacts on ecosystems. The chemical composition of precipitation is directly related to the amount of precipitation; accordingly, it is difficult to identify long-term variation in chemical concentrations. The ratio of the nitrate (NO3−) to non-sea-salt sulfate (nss-SO42−) concentration in precipitation on an equivalent basis (hereinafter, Ratio) is a useful index to investigate the relative contributions of these acidifying species. To identify the long-term record of acidifying species in precipitation over East Asia, the region with the highest emissions worldwide, we compiled ground-based observations of the chemical composition of precipitation over China, Korea, and Japan from 2001 to 2015 based on the Acid Deposition Monitoring Network in East Asia (EANET). The spatial coverage was limited, but additional monitoring data for Japan, southern China, and northern China around Beijing were utilized. The period of analysis was divided into three phases: Phase I (2001–2005), Phase II (2006–2010), and Phase III (2011–2015). The behaviors of NO3− and nss-SO42− concentrations and hence the Ratio in precipitation were related to these precursors. The anthropogenic NOx and SO2 emissions and the NOx ∕ SO2 emission ratio were analyzed. Further, satellite observations of the NO2 and SO2 column density to capture the variation in emissions were applied. We found that the long-term trend in the NO3− concentration in precipitation was not related to the variation in NOx emission and the NO2 column. In comparison, the nss-SO42− concentration in precipitation over China, Korea, and Japan was partially connected to the changes in SO2 emissions from China, but the trends were not significant. The long-term trends of Ratio over China, Korea, and Japan were nearly flat during Phase I, increased significantly during Phase II, and were essentially flat again during Phase III. This variation in Ratio in East Asia clearly corresponded to the NOx ∕ SO2 emission ratio and the NO2 ∕ SO2 column ratio in China. The initial flat trend during Phase I was due to increases in both NOx and SO2 emissions in China, the significantly increasing trend during Phase II was triggered by the increase in NOx emissions and decrease in SO2 emissions in China, and the return to a flat trend during Phase III was caused by declines in both NOx and SO2 emissions in China. These results suggest that emissions in China had a significant impact not only on China but also on downwind precipitation chemistry during the 15-year period of 2001–2015. In terms of wet deposition, the NO3− wet deposition over China, Korea, and Japan did not change dramatically, but the nss-SO42− wet deposition declined over China, Korea, and Japan from Phase II to III. These declines were caused by a strong decrease in the nss-SO42− concentration in precipitation accompanied by a reduction in SO2 emission from China, which counteracted the increase in precipitation. These findings indicated that the acidity of precipitation shifted from sulfur to nitrogen.

We analyzed long-term fine- and coarse-mode synergetic observations of nitrate and related aerosols (SO42−, NO3−, NH4+, Na+, Ca2+) at Fukuoka (33.52° N, 130.47° E) from August 2014 to October 2015. A Goddard Earth Observing System chemical transport model (GEOS-Chem) including dust and sea salt acid uptake processes was used to assess the observed seasonal variation and the impact of long-range transport (LRT) from the Asian continent. For fine aerosols (fSO42−, fNO3−, and fNH4+), numerical results explained the seasonal changes, and a sensitivity analysis excluding Japanese domestic emissions clarified the LRT fraction at Fukuoka (85 % for fSO42−, 47 % for fNO3−, 73 % for fNH4+). Observational data confirmed that coarse NO3− (cNO3−) made up the largest proportion (i.e., 40–55 %) of the total nitrate (defined as the sum of fNO3−, cNO3−, and HNO3) during the winter, while HNO3 gas constituted approximately 40 % of the total nitrate in summer and fNO3− peaked during the winter. Large-scale dust–nitrate (mainly cNO3−) outflow from China to Fukuoka was confirmed during all dust events that occurred between January and June. The modeled cNO3− was in good agreement with observations between July and November (mainly coming from sea salt NO3−). During the winter, however, the model underestimated cNO3− levels compared to the observed levels. The reason for this underestimation was examined statistically using multiple regression analysis (MRA). We used cNa+, nss-cCa2+, and cNH4+ as independent variables to describe the observed cNO3− levels; these variables were considered representative of sea salt cNO3−, dust cNO3−, and cNO3− accompanied by cNH4+), respectively. The MRA results explained the observed seasonal changes in dust cNO3− and indicated that the dust–acid uptake scheme reproduced the observed dust–nitrate levels even in winter. The annual average contributions of each component were 43 % (sea salt cNO3−), 19 % (dust cNO3−), and 38 % (cNH4+ term). The MRA dust–cNO3− component had a high value during the dust season, and the sea salt component made a large contribution throughout the year. During the winter, cNH4+ term made a large contribution. The model did not include aerosol microphysical processes (such as condensation and coagulation between the fine anthropogenic aerosols NO3− and SO42− and coarse particles), and our results suggest that inclusion of aerosol microphysical processes is critical when studying observed cNO3− formation, especially in winter.

A global aerosol reanalysis product named the Japanese Reanalysis for Aerosol (JRAero) was constructed by the Meteorological Research Institute (MRI) of the Japan Meteorological Agency. The reanalysis employs a global aerosol transport model developed by MRI and a two-dimensional variational data assimilation method. It assimilates maps of aerosol optical depth (AOD) from MODIS onboard the Terra and Aqua satellites every 6 h and has a TL159 horizontal resolution (approximately 1.1° × 1.1°). This paper describes the aerosol transport model, the data assimilation system, the observation data, and the setup of the reanalysis and examines its quality with AOD observations. Comparisons with MODIS AODs that were used for the assimilation showed that the reanalysis showed much better agreement than the free run (without assimilation) of the aerosol model and improved under- and overestimation in the free run, thus confirming the accuracy of the data assimilation system. The reanalysis had a root mean square error (RMSE) of 0.05, a correlation coefficient (R) of 0.96, a mean fractional error (MFE) of 23.7 %, a mean fractional bias (MFB) of 2.8 %, and an index of agreement (IOA) of 0.98. The better agreement of the first guess, compared to the free run, indicates that aerosol fields obtained by the reanalysis can improve short-term forecasts. AOD fields from the reanalysis also agreed well with monthly averaged global AODs obtained by the Aerosol Robotic Network (AERONET) (RMSE = 0.08, R = 0. 90, MFE = 28.1 %, MFB = 0.6 %, and IOA = 0.93). Site-by-site comparison showed that the reanalysis was considerably better than the free run; RMSE was less than 0.10 at 86.4 % of the 181 AERONET sites, R was greater than 0.90 at 40.7 % of the sites, and IOA was greater than 0.90 at 43.4 % of the sites. However, the reanalysis tended to have a negative bias at urban sites (in particular, megacities in industrializing countries) and a positive bias at mountain sites, possibly because of insufficient anthropogenic emissions data, the coarse model resolution, and the difference in representativeness between satellite and ground-based observations.

To validate products of the Greenhouse gases Observing SATellite (GOSAT), we observed vertical profiles of aerosols, thin cirrus clouds, and tropospheric ozone with a mobile-lidar system that consisted of a two-wavelength (532 and 1064 nm) polarization lidar and a tropospheric ozone differential absorption lidar (DIAL). We used these lidars to make continuous measurements over Saga (33.24° N, 130.29° E) during 20–31 March 2015. High ozone and high aerosol concentrations were observed almost simultaneously in the altitude range 0.5–1.5 km from 03:00 to 20:00 Japan Standard Time (JST) on 22 March 2015. The maximum ozone volume mixing ratio was ∼ 110 ppbv. The maxima of the aerosol extinction coefficient and optical depth at 532 nm were 1.2 km−1 and 2.1, respectively. Backward trajectory analysis and the simulations by the Model of Aerosol Species IN the Global AtmospheRe (MASINGAR) mk-2 and the Meteorological Research Institute Chemistry-Climate Model, version 2 (MRI-CCM2), indicated that mineral dust particles from the Gobi Desert and an air mass with high ozone and aerosol (mainly sulfate) concentrations that originated from the North China Plain could have been transported over the measurement site within about 2 days. These high ozone and aerosol concentrations impacted surface air quality substantially in the afternoon of 22 March 2015. After some modifications of its physical and chemical parameters, MRI-CCM2 approximately reproduced the high ozone volume mixing ratio. MASINGAR mk-2 successfully predicted high aerosol concentrations, but the predicted peak aerosol optical thickness was about one-third of the observed value.

We present an aerosol data assimilation system based on a global aerosol climate model (SPRINTARS – Spectral Radiation-Transport Model for Aerosol Species) and a four-dimensional variational data assimilation method (4D-Var). Its main purposes are to optimize emission estimates, improve composites, and obtain the best estimate of the radiative effects of aerosols in conjunction with observations. To reduce the huge computational cost caused by the iterative integrations in the models, we developed an offline model and a corresponding adjoint model, which are driven by pre-calculated meteorological, land, and soil data. The offline and adjoint model shortened the computational time of the inner loop by more than 30%. By comparing the results with a 1 yr simulation from the original online model, the consistency of the offline model was verified, with correlation coefficient R > 0.97 and absolute value of normalized mean bias NMB < 7% for the natural aerosol emissions and aerosol optical thickness (AOT) of individual aerosol species. Deviations between the offline and original online models are mainly associated with the time interpolation of the input meteorological variables in the offline model; the smaller variability and difference in the wind velocity near the surface and relative humidity cause negative and positive biases in the wind-blown aerosol emissions and AOTs of hygroscopic aerosols, respectively. The feasibility and capability of the developed system for aerosol inverse modelling was demonstrated in several inversion experiments based on the observing system simulation experiment framework. In the experiments, we used the simulated observation data sets of fine- and coarse-mode AOTs from sun-synchronous polar orbits to investigate the impact of the observational frequency (number of satellites) and coverage (land and ocean), and assigned aerosol emissions to control parameters. Observations over land have a notably positive impact on the performance of inverse modelling as compared with observations over ocean, implying that reliable observational information over land is important for inverse modelling of land-born aerosols. The experimental results also indicate that information that provides differentiations between aerosol species is crucial to inverse modelling over regions where various aerosol species coexist (e.g. industrialized regions and areas downwind of them).

Anthropogenic SO2 emissions increased alongside economic development in China at a rate of 12.7% yr−1 from 2000 to 2005. However, under new Chinese government policy, SO2 emissions declined by 3.9% yr−1 between 2005 and 2009. Between 2000 and 2010, we found that the variability in the fine-mode (submicron) aerosol optical depth (AOD) over the oceans adjacent to East Asia increased by 3–8% yr−1 to a peak around 2005–2006 and subsequently decreased by 2–7% yr−1, based on observations by the Moderate Resolution Imaging Spectroradiometer (MODIS) on board NASA's Terra satellite and simulations by a chemical transport model. This trend is consistent with ground-based observations of aerosol particles at a mountainous background observation site in central Japan. These fluctuations in SO2 emission intensity and fine-mode AOD are thought to reflect the widespread installation of fuel-gas desulfurization (FGD) devices in power plants in China, because aerosol sulfate is a major determinant of the fine-mode AOD in East Asia. Using a chemical transport model, we confirmed that the contribution of particulate sulfate to the fine-mode AOD is more than 70% of the annual mean and that the abovementioned fluctuation in fine-mode AOD is caused mainly by changes in SO2 emission rather than by other factors such as varying meteorological conditions in East Asia. A strong correlation was also found between satellite-retrieved SO2 vertical column density and bottom-up SO2 emissions, both of which were also consistent with observed fine-mode AOD trends. We propose a simplified approach for evaluating changes in SO2 emissions in China, combining the use of modeled sensitivity coefficients that describe the variation of fine-mode AOD with changes in SO2 emissions and satellite retrieval. Satellite measurements of fine-mode AOD above the Sea of Japan marked a 4.1% yr−1 decline between 2007 and 2010, which corresponded to the 9% yr−1 decline in SO2 emissions from China during the same period.

The NASA space-borne Mie-lidar system CALIPSO/CALIOP revealed that multiple large Asian dust layers with a horizontal scale of 2000–3000 km reached North America, occupying the full troposphere, in April 2010. This kind of dust layer transport has not been reported before. Our analysis of CALIOP data and global aerosol model results revealed that frequent dust emissions occurred in northwestern China because of stronger-than-average near-surface winds, and that strong stable westerly winds carried the Asian dust from northwestern China to the central Pacific Ocean. A negative pressure anomaly was located in the eastern Pacific Ocean, and the main dust transport path was split into two branches: a northern path and a southern path over North America. Northern-path dust was trapped and stagnant for a longer time than southern path dust and finally subsided under a high-pressure system. Dust along the southern path reached the central US. These complex conditions resulted in a multi-layered structure of dust over North America.

An intense dust storm occurred during 19–20 May 2007 over the Taklimakan Desert in northwestern China. Over the following days, the space-borne lidar CALIOP tracked an optically thin, highly elevated, horizontally extensive dust veil that was transported intercontinentally over eastern Asia, the Pacific Ocean, North America, and the Atlantic Ocean. A global aerosol transport model (SPRINTARS) simulated the dust veil quite well and provided a three-dimensional view of the intercontinental dust transport. The SPRINTARS simulation revealed that the dust veil traveled at 4–10 km altitudes with a thickness of 1–4 km along the isentropic surface between 310 and 340 K. The transport speed was about 1500 km/day. The estimated dust amount exported to the Pacific was 30.8 Gg, of which 65% was deposited in the Pacific and 18% was transported to the North Atlantic. These results imply that dust veils can fertilize open oceans, add to background dust, and affect the radiative budget at high altitudes through scattering and absorption. The injection mechanism that lifts dust particles into the free atmosphere is important for understanding the formation of the dust veil and subsequent long-range transport. We used a regional dust transport model (RC4) to analyze the dust emission and injection over the source region. The RC4 analysis revealed that strong northeasterly surface winds associated with low pressures invaded the Taklimakan Desert through the eastern corridor. These winds then formed strong upslope wind along the high, steep mountainsides of the Tibetan Plateau and blew large amounts of dust into the air. The updraft lifted the dust particles farther into the upper troposphere (about 9 km above mean sea level, MSL), where westerlies are generally present. The unusual terrain surrounding the Taklimakan Desert played a key role in the injection of dust to the upper troposphere to form the dust veil.

Detailed 3-D structures of Trans-Pacific Asian dust transport occurring during 5–15 May 2007 were investigated using the NASA/CALIOP vertical-resolved measurements and a three-dimensional aerosol model (SPRINTARS). Both CALIOP and SPRINTARS dust extinctions showed a good agreement along the way of the transport from the dust source regions across North Pacific into North America. A vertically two-layered dust distribution was observed over the northeastern Pacific and North America. The lower dust layer originated from a dust storm generated in the Gobi Desert on 5 May. It was transported at an altitude of around 4 km MSL and has mixed with Asian anthropogenic air pollutants during the course of transport. The upper dust layer mainly originated from a dust storm that occurred in the Taklimakan Desert 2–3 days after the Gobi dust storm generation. The upper dust cloud was transported in higher altitudes above the major clouds layer during the Trans-Pacific transport. It therefore has remained unmixed with the Asian air pollutants and almost unaffected by wet removal. The decay of its concentration level was small (only one-half after its long-distance transport crossing the Pacific). Our dust budget analysis revealed that the Asian dust flux passing through the longitude plane of 140° E was 2.1 Tg, and one third of that arrived North America. The cases analyzed in this study revealed that, while the Gobi Desert is an important source that can contribute to the long-range dust transport, the Taklimakan Desert appears to be another important source that can contribute to the dust transport occurring particularly at high altitudes.

Three-dimensional structures of Asian dust transport in the planetary boundary layer (PBL) and free atmosphere occurring successively during the end of May 2007 were clarified using results of space-borne backscatter lidar, Cloud-Aerosol Lidar with Orthogonal Polarization (CALIOP), and results obtained using a data-assimilated version of a dust transport model (RC4) based on a ground-based NIES lidar network. The dust layer depths and the vertical and horizontal structure simulated by RC4 agreed with those of CALIOP observations from the dust source region to the far-downstream region. Two important transport mechanisms of Asian dust in the PBL and free atmosphere were clarified: a low-level dust outbreak within the dry slot region of a well-developed low-pressure system, and formation of an elevated dust layer within the warm sector of a low-pressure system. We also represent the aging of pure dust particles using the particle depolarization ratio (PDR) at 532 nm and the color ratio (CR) at 1064 nm and 532 nm. Aerosols with high PDR were observed uniformly over the dust source region. While the dust cloud was transported to the eastern downwind regions, aerosols with low PDR and high CR occur in the layer of less than 1 km height, suggesting a mixing state of spherical aerosols and dust in the surface layer.

Simultaneous ground-based measurements of ozone (O3) and carbon monoxide (CO) were conducted in March 2005 as part of the East Asian Regional Experiment (EAREX) 2005 under the umbrella of the Atmospheric Brown Clouds (ABC) project. Multiple air quality monitoring networks were integrated by performing intercomparison of individual calibration standards and measurement techniques to ensure comparability of ambient measurements, along with providing consistently high time-resolution measurements of O3 and CO at the surface sites in East Asia. Ambient data collected from eight surface stations were compared with simulation results obtained by a regional chemistry transport model to infer recent changes in CO emissions from East Asia. Our inverse estimates of the CO emissions from China up to 2005 suggested an increase of 16% since 2001, in good agreement with the recent MOPITT satellite observations and the bottom-up estimates up to 2006. The O3 enhancement relative to CO in continental pollution plumes traversed in the boundary layer were examined as a function of transport time from the Asian continent to the western Pacific Ocean. The observed ΔO3/ΔCO ratios show increasing tendency during eastward transport events due likely to en-route photochemical O3 formation, suggesting that East Asia is an important O3 source region during spring.

A four-dimensional variational (4D-Var) data assimilation system for a regional dust model (RAMS/CFORS-4DVAR; RC4) is applied to an adjoint inversion of a heavy dust event over eastern Asia during 20 March–4 April 2007. The vertical profiles of the dust extinction coefficients derived from NIES Lidar network are directly assimilated, with validation using observation data. Two experiments assess impacts of observation site selection: Experiment A uses five Japanese observation sites located downwind of dust source regions; Experiment B uses these and two other sites near source regions. Assimilation improves the modeled dust extinction coefficients. Experiment A and Experiment B assimilation results are mutually consistent, indicating that observations of Experiment A distributed over Japan can provide comprehensive information related to dust emission inversion. Time series data of dust AOT calculated using modeled and Lidar dust extinction coefficients improve the model results. At Seoul, Matsue, and Toyama, assimilation reduces the root mean square differences of dust AOT by 35–40%. However, at Beijing and Tsukuba, the RMS differences degrade because of fewer observations during the heavy dust event. Vertical profiles of the dust layer observed by CALIPSO are compared with assimilation results. The dense dust layer was trapped at potential temperatures (θ) of 280–300 K and was higher toward the north; the model reproduces those characteristics well. Latitudinal distributions of modeled dust AOT along the CALIPSO orbit paths agree well with those of CALIPSO dust AOT, OMI AI, and MODIS coarse-mode AOT, capturing the latitude at which AOTs and AI have high values. Assimilation results show increased dust emissions over the Gobi Desert and Mongolia; especially for 29–30 March, emission flux is about 10 times greater. Strong dust uplift fluxes over the Gobi Desert and Mongolia cause the heavy dust event. Total optimized dust emissions are 57.9 Tg (Experiment A; 57.8% larger than before assimilation) and 56.3 Tg (Experiment B; 53.4% larger).

c-Myc is a proto-oncoprotein that regulates various cellular processes and whose abnormal expression leads to tumorigenesis. c-Myc protein stability has been shown to be predominantly controlled by the ubiquitin ligase (E3) CRL1 Fbxw7 in a manner dependent on glycogen synthase kinase 3 (GSK3)-mediated phosphorylation. Here we show that, in some types of cancer cells, c-Myc degradation is largely insensitive to the GSK3 inhibitor (GSK3i) CHIR99021, suggesting the existence of an E3 other than CRL1 Fbxw7 for c-Myc degradation. Mass spectrometry identified CRL2 KLHDC3 as such an E3. In GSK3i-insensitive cancer cells, combined depletion of Fbxw7 and KLHDC3 resulted in marked stabilization of c-Myc, suggestive of a cooperative action of Fbxw7 and KLHDC3. Furthermore, transplantation of such cells deficient in both Fbxw7 and KLHDC3 into immunodeficient mice gave rise to larger tumors compared with those formed by cells lacking only Fbxw7. GSK3i-insensitive pancreatic cancer cells expressed lower levels of SHISA2, a negative regulator of the Wnt signaling pathway, than did GSK3i-sensitive cells. KLHDC3 mRNA abundance was associated with prognosis in pancreatic cancer patients with a low level of SHISA2 gene expression. These results suggest that KLHDC3 cooperates with Fbxw7 to promote c-Myc degradation in a subset of cancer cells with low GSK3 activity., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

C-C chemokine receptor type 2 (CCR2) is the receptor for C-C motif chemokine 2 (CCL2) and is associated with various inflammatory diseases and cancer metastasis. Although many inhibitors for CCR2 have been developed, it remains unresolved which inhibitors are the most effective in the clinical setting. In the present study, we compared 10 existing human CCR2 antagonists in a calcium influx assay using human monocytic leukemia cells. Among them, MK0812 was found to be the most potent inhibitor of human CCR2. Furthermore, we generated a human CCR2B knock-in mouse model to test the efficacy of MK0812 against a lung metastasis model of breast cancer. Oral administration of MK0812 to humanized mice did indeed reduce the number of monocytic myeloid-derived suppressor cells and the rate of lung metastasis. These results suggest that MK0812 is the most promising candidate among the commercially available CCR2 inhibitors. We propose that combining these two screening methods may provide an excellent experimental method for identifying effective drugs that inhibit human CCR2., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Developing CD4 + CD8 + double-positive (DP) thymocytes with randomly generated T cell receptors (TCRs) undergo positive (maturation) or negative (apoptosis) selection on the basis of the strength of TCR stimulation. Selection fate is determined by engagement of TCR ligands with a subtle difference in affinity, but the molecular details of TCR signaling leading to the different selection outcomes have remained unclear. We performed phosphoproteome analysis of DP thymocytes and found that p90 ribosomal protein kinase (RSK) phosphorylation at Thr 562 was induced specifically by high-affinity peptide ligands. Such phosphorylation of RSK triggered its translocation to the nucleus, where it phosphorylated the nuclear receptor Nur77 and thereby promoted its mitochondrial translocation for apoptosis induction. Inhibition of RSK activity protected DP thymocytes from antigen-induced cell death. We propose that RSK phosphorylation constitutes a mechanism by which DP thymocytes generate a stepwise and binary signal in response to exposure to TCR ligands with a graded affinity., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Reactive oxygen species (ROS) posed a risk for the transition of vertebrates from aquatic to terrestrial life. How ancestral organisms adapted to such ROS exposure has remained a mystery. Here, we show that attenuation of the activity of the ubiquitin ligase CRL3Keap1 for the transcription factor Nrf2 during evolution was key to development of an efficient response to ROS exposure. The Keap1 gene was duplicated in fish to give rise to Keap1A and the only remaining mammalian paralog Keap1B, the latter of which shows a lower affinity for Cul3 and contributes to robust Nrf2 induction in response to ROS exposure. Mutation of mammalian Keap1 to resemble zebrafish Keap1A resulted in an attenuated Nrf2 response, and most knock-in mice expressing such a Keap1 mutant died on exposure as neonates to sunlight-level ultraviolet radiation. Our results suggest that molecular evolution of Keap1 was essential for adaptation to terrestrial life.

To improve the predictability of concentrations of atmospheric particulate matter, a data assimilation (DA) system using ensemble square root filter (EnSRF) has been developed for the Community Multiscale Air Quality (CMAQ) model. The EnSRF DA method is a deterministic variant of the ensemble Kalman filter (EnKF) method, which means that unlike the EnKF method, it does not add random noise to the observations. To compare the performances of the EnSRF with those of other DA methods, such as EnKF and 3DVAR (three-dimensional variational), these three methods were applied to the same CMAQ model simulations with identical experimental settings. This is the first attempt in the field of chemical DA to compare the EnKF and EnSRF methods. An identical set of surface fine particulate matter (PM 2.5 ) were assimilated every 6 h by all the DA methods over a CMAQ domain of East Asia, during the period from 01 May to 11 June 2016. In parallel with 'reanalysis experiments', we also carried out '48 h prediction experiments' using the optimized initial conditions produced by the three DA methods. Detailed analyses among the three DA methods were then carried out by comparing both the reanalysis and the prediction outputs with the observed surface PM 2.5 over four regions (i.e., South Korea, the Beijing-Tianjin-Hebei (BTH) region, Shandong province, and Liaoning province). The comparison results revealed that the EnSRF produced the best reanalysis and prediction fields in terms of several statistical metrics. For example, when the 3DVAR, EnKF, and EnSRF methods were used, averaged normalized mean biases (NMBs) decreased by (57.6, 85.6, and 91.8) % in reanalyses and (39.7, 87.6, and 91.5) % in first-day predictions, compared to the CMAQ control experiment (i.e., without DA) over South Korea, respectively. Also, over the three Chinese regions, the EnSRF method outperformed the EnKF and 3DVAR methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Simple dual-wavelength high-spectral-resolution lidar at 355 and 532 nm with a scanning interferometer was developed for continuous observations of aerosol profiles. Scanning the interferometer periodically over a range of one fringe at 532 nm (1.5 fringes at 355 nm) enabled recording of range-resolved interference signals at these two wavelengths. Reference signals taken from the transmitted laser were used to correct the interference phase shift due to laser frequency variation for every scan. Profiles of aerosol backscatter and extinction coefficients were retrieved from range-resolved interference data. One month of continuous measurements demonstrated the robustness of the system.

The lockdown measures due to COVID-19 affected the industry, transportation and other human activities within China in early 2020, and subsequently the emissions of air pollutants. The decrease of atmospheric NO 2 due to the COVID-19 lockdown and other factors were quantitively analyzed based on the surface concentrations by in-situ observations, the tropospheric vertical column densities (VCDs) by different satellite retrievals including OMI and TROPOMI, and the model simulations by GEOS-Chem. The results indicated that due to the COVID-19 lockdown, the surface NO 2 concentrations decreased by 42% ± 8% and 26% ± 9% over China in February and March 2020, respectively. The tropospheric NO 2 VCDs based on both OMI and high quality (quality assurance value (QA) ≥ 0.75) TROPOMI showed similar results as the surface NO 2 concentrations. The daily variations of atmospheric NO 2 during the first quarter (Q1) of 2020 were not only affected by the COVID-19 lockdown, but also by the Spring Festival (SF) holiday (January 24-30, 2020) as well as the meteorology changes due to seasonal transition. The SF holiday effect resulted in a NO 2 reduction from 8 days before SF to 21 days after it (i.e. January 17 - February 15), with a maximum of 37%. From the 6 days after SF (January 31) to the end of March, the COVID-19 lockdown played an important role in the NO 2 reduction, with a maximum of 51%. The meteorology changes due to seasonal transition resulted in a nearly linear decreasing trend of 25% and 40% reduction over the 90 days for the NO 2 concentrations and VCDs, respectively. Comparisons between different datasets indicated that medium quality (QA ≥ 0.5) TROPOMI retrievals might suffer large biases in some periods, and thus attention must be paid when they are used for analyses, data assimilations and emission inversions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Elsevier Ltd. All rights reserved.)

FBXW7 (also known as Fbw7, Sel10, hCDC4, or hAgo) is a tumor suppressor and the most frequently mutated member of the F-box protein family in human cancers. FBXW7 functions as the substrate recognition component of an SCF-type E3 ubiquitin ligase. It specifically controls the proteasome-mediated degradation of many oncoproteins such as c-MYC, NOTCH, KLF5, cyclin E, c-JUN, and MCL1. In this review, we summarize the molecular and biological features of FBXW7 and its substrates as well as the impact of mutations of FBXW7 on cancer development. We also address the clinical potential of anticancer therapy targeting FBXW7., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Controlled protein degradation is essential for the operation of a variety of cellular processes including cell division, growth, and differentiation. Identification of the relations between ubiquitin ligases and their substrates is key to understanding the molecular basis of cancer development and to the discovery of novel targets for cancer therapeutics. F-box proteins function as the substrate recognition subunits of S-phase kinase-associated protein 1 (SKP1)-Cullin1 (CUL1)-F-box protein (SCF) ubiquitin ligase complexes. Here, we summarize the roles of specific F-box proteins that have been shown to function as tumor promoters or suppressors. We also highlight proto-oncoproteins that are targeted for ubiquitylation by multiple F-box proteins, and discuss how these F-box proteins are deployed to regulate their cognate substrates in various situations.

A rapid decrease in PM 2.5 concentrations in China has been observed in response to the enactment of strong emission control policies. From 2012 to 2017, total emissions of SO 2 and NO x from China decreased by approximately 63% and 24%, respectively. Simultaneously, decreases in the PM 2.5 concentration in Japan have been observed since 2014, and the proportion of stations that satisfy the PM 2.5 environmental standard (daily, 35 µg/m 3 ; annual average, 15 µg/m 3 ) increased from 37.8% in fiscal year (FY) 2014 (April 2014 to March 2015) to 89.9% in FY 2017. However, the quantitative relationship between the PM 2.5 improvement in China and the PM 2.5 concentration in downwind regions is not well understood. Here, we (1) quantitatively evaluate the impacts of Chinese environmental improvements on downwind areas using source/receptor analysis with a chemical transport model, and (2) show that these rapid emissions reductions improved PM 2.5 concentrations both in China and its downwind regions, but the difference between SO 2 and NO x reduction rates led to greater production of nitrates (e.g., NH 4 NO 3 ) due to a chemical imbalance in the ammonia-nitric acid-sulfuric acid-water system. Observations from a clean remote island in western Japan and numerical modeling confirmed this paradigm shift.

Since the first International Cooperative for Aerosol Prediction (ICAP) multi-model ensemble (MME) study, the number of ICAP global operational aerosol models has increased from five to nine. An update of the current ICAP status is provided, along with an evaluation of the performance of ICAP-MME over 2012-2017, with a focus on June 2016-May 2017. Evaluated with ground-based Aerosol Robotic Network (AERONET) aerosol optical depth (AOD) and data assimilation quality MODerate-resolution Imaging Spectroradiometer (MODIS) retrieval products, the ICAP-MME AOD consensus remains the overall top-scoring and most consistent performer among all models in terms of root-mean-square error (RMSE), bias and correlation for total, fine- and coarse-mode AODs as well as dust AOD; this is similar to the first ICAP-MME study. Further, over the years, the performance of ICAP-MME is relatively stable and reliable compared to more variability in the individual models. The extent to which the AOD forecast error of ICAP-MME can be predicted is also examined. Leading predictors are found to be the consensus mean and spread. Regression models of absolute forecast errors were built for AOD forecasts of different lengths for potential applications. ICAP-MME performance in terms of modal AOD RMSEs of the 21 regionally representative sites over 2012-2017 suggests a general tendency for model improvements in fine-mode AOD, especially over Asia. No significant improvement in coarse-mode AOD is found overall for this time period., (© 2019 The Authors. Quarterly Journal of the Royal Meteorological Society published by John Wiley & Sons Ltd on behalf of the Royal Meteorological Society.)

Inflammation plays an essential role in the development and progression of most cancers. Chemokine C-C motif chemokine 2 (CCL2) and its receptor C-C chemokine receptor type 2 (CCR2) constitute a key signaling axis in inflammation that has recently attracted much interest on the basis of evidence showing its association with cancer progression. Propagermanium (3-oxygermylpropionic acid polymer) is an organogermanium compound that is given for the treatment of hepatitis B in Japan and which inhibits the CCL2-CCR2 signaling pathway. Herein, we review the importance of the CCL2-CCR2 axis as a target in cancer treatment as shown by studies in mice and humans with pharmacological agents including propagermanium., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The biological relation between ubiquitin ligases and their substrates has been largely unclear. We previously developed a method-differential proteomics-based identification of ubiquitylation substrates (DiPIUS)-for the comprehensive identification of substrates for a given ubiquitin ligase. We have now applied DiPIUS to the F-box protein Fbxw7 in three cell lines (mHepa, Neuro2A and C2C12) and thereby identified Krüppel-like factor 7 (KLF7) as a candidate substrate of the SCF Fbxw7 ubiquitin ligase complex. KLF7 was shown to interact with Fbxw7 and to undergo Fbxw7-mediated polyubiquitylation. The stability of KLF7 was increased by depletion of Fbxw7, mutation of a putative Cdc4 phosphodegron (CPD) of KLF7 or exposure to inhibitors of glycogen synthase kinase-3 (GSK-3). Over-expression of Fbxw7 in Neuro2A cells down-regulated expression of the p21 Cip1 gene, which is a transcriptional target of KLF7 in neuronal differentiation and maintenance. Despite the presence of an almost identical CPD sequence in KLF6, the closest paralog of KLF7, mutation of this sequence affected neither the interaction of KLF6 with Fbxw7 nor its half-life. Our results suggest that KLF7, but not KLF6, is a bona fide substrate of SCF Fbxw7 , and that control of KLF7 abundance by SCF Fbxw7 might contribute to the regulation of neuronal differentiation and maintenance., (© 2019 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

The Taklimakan Desert is known to be one of the world's major sources of aeolian dust particles. Continuous images with 10-min temporal and 2-km spatial resolutions from a new-generation geostationary meteorological satellite captured the lifecycle (generation, evolution and outflow) of a previously unrecognized type of Taklimakan dust storm. The dust storm showed an anti-clockwise spiral structure and a clear core and behaved like a "dust vortex". From image analysis, the horizontal scale and temporal lifetime of the dust vortex were estimated to be 600 km and 36 hours, respectively. We found that a strong pressure trough (cut-off low), along with a cold air mass located on the northwestern side of the Taklimakan Desert and the high mountains surrounding the Taklimakan Desert, played important roles in the formation and evolution of the dust vortex.

The ubiquitin-proteasome system regulates the abundance of many cellular proteins by mediating their targeted degradation. We previously developed a method-differential proteomics-based identification of ubiquitylation substrates (DiPIUS)-for the comprehensive identification of substrates for a given F-box protein subunit of SCF-type ubiquitin ligases. We have now applied DiPIUS to the F-box protein Fbxw7 in three cell lines (mHepa, Neuro2A, and C2C12) and thereby identified myelin regulatory factor (MyRF), an endoplasmic reticulum-anchored transcription factor that is essential for myelination of nerves in the central nervous system, as a candidate substrate of Fbxw7 specifically in mHepa cells. Co-immunoprecipitation analysis confirmed that the NH 2 -terminal cytoplasmic domain of MyRF interacted with Fbxw7 in these cells. Furthermore, an in vitro ubiquitylation assay revealed that MyRF undergoes polyubiquitylation in the presence of purified recombinant SCF Fbxw7 In addition, the stability of MyRF in mHepa cells was increased by mutation of a putative phosphodegron sequence or by exposure of the cells to an inhibitor of glycogen synthase kinase-3 (GSK-3). We found that MyRF mRNA is not restricted to the central nervous system but is instead distributed widely among mouse tissues. Furthermore, with the use of RNA sequencing in mHepa cells overexpressing or depleted of MyRF, we identified many novel potential target genes of MyRF. Our results thus suggest that Fbxw7 controls the transcription of MyRF target genes in various tissues through regulation of MyRF protein stability in a manner dependent on MyRF phosphorylation by GSK-3., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Appropriate policies to improve air quality by reducing anthropogenic emissions are urgently needed. This is typified by the particulate matter (PM) problem and it is well known that one type of PM, sulfate aerosol (SO 4 2- ), has a large-scale impact due to long range transport. In this study we evaluate the source-receptor relationships of SO 4 2- over East Asia for 2005, when anthropogenic sulfur dioxide (SO 2 ) emissions from China peaked. SO 2 emissions from China have been declining since 2005-2006, so the possible maximum impact of Chinese contributions of SO 4 2- is evaluated. This kind of information provides a foundation for policy making and the estimation of control effects. The tagged tracer method was applied to estimate the source apportionment of SO 4 2- for 31 Chinese province-scale regions. In addition, overall one-year source apportionments were evaluated to clarify the seasonal dependency. Model performance was confirmed by comparing with ground-based observations over mainland China, Taiwan, Korea, and Japan, and the model results fully satisfied the performance goal for PM. We found the following results. Shandong and Hebei provinces, which were the largest and second largest SO 2 sources in China, had the greatest impact over the whole of East Asia with apportionments of around 10-30% locally and around 5-15% in downwind receptor regions during the year. Despite large SO 2 emissions, the impact of south China (e.g., Guizhou, Guangdong, and Sichuan provinces) was limited to local impact. These results suggest that the reduction policy in south China contributes to improving the local air quality, whereas policies in north and central China are beneficial for both the whole of China and downwind regions. Over Taiwan, Korea, and Japan, the impact of China was dominant; however, local contributions were important during summer., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The amount of 137 Cs released by the Fukushima Dai-ichi Nuclear Power Plant accident of 11 March 2011 was inversely estimated by integrating an atmospheric dispersion model, an a priori source term, and map of deposition recorded by aircraft. An a posteriori source term refined finer (hourly) variations comparing with the a priori term, and estimated 137 Cs released 11 March to 2 April to be 8.12 PBq. Although time series of the a posteriori source term was generally similar to those of the a priori source term, notable modifications were found in the periods when the a posteriori source term was well-constrained by the observations. Spatial pattern of 137 Cs deposition with the a posteriori source term showed better agreement with the 137 Cs deposition monitored by aircraft. The a posteriori source term increased 137 Cs deposition in the Naka-dori region (the central part of Fukushima Prefecture) by 32.9%, and considerably improved the underestimated a priori 137 Cs deposition. Observed values of deposition measured at 16 stations and surface atmospheric concentrations collected on a filter tape of suspended particulate matter were used for validation of the a posteriori results. A great improvement was found in surface atmospheric concentration on 15 March; the a posteriori source term reduced root mean square error, normalized mean error, and normalized mean bias by 13.4, 22.3, and 92.0% for the hourly values, respectively. However, limited improvements were observed in some periods and areas due to the difficulty in simulating accurate wind fields and the lack of the observational constraints., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

How stem cells maintain their stemness or initiate exit from the stem cell state for differentiation remains largely unknown. Aldehyde dehydrogenase (ALDH) activity is a hallmark of stem cells-including embryonic, adult tissue, and cancer stem cells-and is essential for their maintenance. The mechanisms by which ALDH activity is regulated in stem cells have remained poorly understood, however. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Most mice deficient in FBXL12 died during the embryonic or perinatal period probably as a result of abnormal development of the placenta, characterized by impaired formation of the junctional zone. ALDH3 accumulated in the FBXL12-deficient placenta, and forced expression of ALDH3 in wild-type TSCs phenocopied the differentiation defect of FBXL12-deficient TSCs. Conversely, inhibition of ALDH3 activity by gossypol rescued the phenotype of FBXL12 deficiency. Our results suggest that FBXL12 plays a key role in the downregulation of ALDH3 activity in TSCs and thereby initiates trophoblast differentiation during placental development., (© 2015 AlphaMed Press.)

Although identification of substrates for ubiquitin ligase (E3) is important for understanding its biological functions, detection of the interaction between an E3 and its substrates has remained challenging. We recently developed a new approach, termed differential proteomics-based identification of ubiquitylation substrates (DiPIUS), for the discovery of substrates of a given E3 ligase. We have now applied this approach to an uncharacterized human F-box protein, FBXO21, which serves as the substrate-recognition subunit of a SKP1-CUL1-F-box protein (SCF)-type E3, thereby identifying EID1 (EP300-interacting inhibitor of differentiation 1) as a candidate substrate. The central and COOH-terminal portion of FBXO21 was found to interact with the COOH-terminal region of EID1 in transfected cells. Over-expression of FBXO21 resulted in the down-regulation of EID1, whereas disruption of the FBXO21 gene with the CRISPR/Cas9 system stabilized EID1 and led to its accumulation in both the cytoplasm and nucleus. An in vitro ubiquitylation assay showed that EID1 is a direct substrate of SCF(FBXO)(21). Collectively, our results suggest that EID1 is a bona fide substrate of FBXO21 and that the control of EID1 abundance by SCF(FBXO)(21) might affect the transcriptional repression activity of EID1., (© 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.)

Fbxw7 has been identified as an oncosuppressor protein in many types of cancer. We have recently shown that loss of Fbxw7 in bone marrow-derived stromal cells (BMSCs) promotes cancer metastasis by increasing production of the chemokine CCL2, which attracts monocytic myeloid-derived suppressor cells (Mo-MDSCs) and macrophages to the metastatic niche.

A GATA family transcription factor, GATA-binding protein 2 (GATA2), participates in cell growth and differentiation of various cells, such as hematopoietic stem cells. Although its expression level is controlled by transcriptional induction and proteolytic degradation, the responsible E3 ligase has not been identified. Here, we demonstrate that F-box/WD repeat-containing protein 7 (Fbw7/Fbxw7), a component of Skp1, Cullin 1, F-box-containing complex (SCF)-type E3 ligase, is an E3 ligase for GATA2. GATA2 contains a cell division control protein 4 (Cdc4) phosphodegron (CPD), a consensus motif for ubiquitylation by Fbw7, which includes Thr(176). Ectopic expression of Fbw7 destabilized GATA2 and promoted its proteasomal degradation. Substitution of threonine 176 to alanine in GATA2 inhibited binding with Fbw7, and the ubiquitylation and degradation of GATA2 by Fbw7 was suppressed. The CPD kinase, which mediates the phosphorylation of Thr(176), was cyclin B-cyclin-dependent kinase 1 (CDK1). Moreover, depletion of endogenous Fbw7 stabilized endogenous GATA2 in K562 cells. Conditional Fbw7 depletion in mice increased GATA2 levels in hematopoietic stem cells and myeloid progenitors at the early stage. Increased GATA2 levels in Fbw7-conditional knock-out mice were correlated with a decrease in a c-Kit high expressing population of myeloid progenitor cells. Our results suggest that Fbw7 is a bona fide E3 ubiquitin ligase for GATA2 in vivo., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

The gene encoding F-box protein FBXW7 is frequently mutated in many human cancers. Although most previous studies have focused on the tumor-suppressive capacity of FBXW7 in tumor cells themselves, we determined that FBXW7 in the host microenvironment also suppresses cancer metastasis. Deletion of Fbxw7 in murine BM-derived stromal cells induced accumulation of NOTCH and consequent transcriptional activation of Ccl2. FBXW7-deficient mice exhibited increased serum levels of the chemokine CCL2, which resulted in the recruitment of both monocytic myeloid-derived suppressor cells and macrophages, thereby promoting metastatic tumor growth. Administration of a CCL2 receptor antagonist blocked the enhancement of metastasis in FBXW7-deficient mice. Furthermore, in human breast cancer patients, FBXW7 expression in peripheral blood was associated with serum CCL2 concentration and disease prognosis. Together, these results suggest that FBXW7 antagonizes cancer development in not only a cell-autonomous manner, but also a non-cell-autonomous manner, and that modulation of the FBXW7/NOTCH/CCL2 axis may provide a potential approach to suppression of cancer metastasis.

Carbon monoxide (CO) emissions in China in 2005-2010 were estimated by inversion, using the Green's function method from vertical CO profiles derived from MOPITT Version 5 satellite data and a tagged CO simulation, and validated with independent in situ observations from the World Data Centre for Greenhouse Gases. Modeling with a posteriori emission successfully reproduced CO outflow from the continent to the East China Sea, Sea of Japan, and Japanese islands during winter and spring, and compensated for underestimates in central and eastern China in summer. A posteriori emissions showed large seasonal variations in which December and March emissions were on average 23% larger than August emissions, consistent with other studies. Estimated Chinese CO emissions were 184.4, 173.1, 184.6, 158.4, 157.4, and 157.3 Tg/year for 2005-2010, respectively. The decrease after 2007 is partly attributed to Chinese socioeconomic conditions and improved combustion efficiency., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

MDM2 mediates the ubiquitylation and thereby triggers the proteasomal degradation of the tumor suppressor protein p53. However, genetic evidence suggests that MDM2 contributes to multiple regulatory networks independently of p53 degradation. We have now identified the DEAD-box RNA helicase DDX24 as a nucleolar protein that interacts with MDM2. DDX24 was found to bind to the central region of MDM2, resulting in the polyubiquitylation of DDX24 both in vitro and in vivo. Unexpectedly, however, the polyubiquitylation of DDX24 did not elicit its proteasomal degradation but rather promoted its association with preribosomal ribonucleoprotein (pre-rRNP) processing complexes that are required for the early steps of pre-rRNA processing. Consistently with these findings, depletion of DDX24 in cells impaired pre-rRNA processing and resulted both in abrogation of MDM2 function and in consequent p53 stabilization. Our results thus suggest an unexpected role of MDM2 in the nonproteolytic ubiquitylation of DDX24, which may contribute to the regulation of pre-rRNA processing., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

The Skp1-Cul1-F-box protein (SCF) complex is one of the most well characterized types of ubiquitin ligase (E3), with the E3 activity of the complex being regulated in part at the level of complex formation. Fbxl3 is an F-box protein that is responsible for the ubiquitylation and consequent degradation of cryptochromes (Crys) and thus regulates oscillation of the circadian clock. Here we show that formation of the SCF(Fbxl3) complex is regulated by substrate binding in vivo. Fbxl3 did not associate with Skp1 and Cul1 to a substantial extent in transfected mammalian cells. Unexpectedly, however, formation of the SCF(Fbxl3) complex was markedly promoted by forced expression of its substrate Cry1 in these cells. A mutant form of Fbxl3 that does not bind to Cry1 was unable to form an SCF complex, suggesting that interaction of Cry1 with Fbxl3 is essential for formation of SCF(Fbxl3). In contrast, recombinant Fbxl3 associated with recombinant Skp1 and Cul1 in vitro even in the absence of recombinant Cry1. Domain-swap analysis revealed that the COOH-terminal leucine-rich repeat domain of Fbxl3 attenuates the interaction of Skp1, suggesting that a yet unknown protein associated with the COOH-terminal domain of Fbxl3 and inhibited SCF complex formation. Our results thus provide important insight into the regulation of both SCF ubiquitin ligase activity and circadian rhythmicity.

Although identification of substrates for an enzyme is a key step in elucidation of its biological functions, detection of the interaction between enzymes and substrates remains challenging. We recently developed a new approach, termed differential proteomics-based identification of ubiquitylation substrates (DiPIUS), for the discovery of substrates of ubiquitin ligases. We have now applied this approach to Fbxw7, the F-box protein component of an Skp1-Cul1-F-box protein-type ubiquitin ligase and, thereby, identified two similar transcription factors, old astrocyte specifically induced substance (OASIS) and BBF2 human homolog on chromosome 7 (BBF2H7), as candidate substrates. Coimmunoprecipitation analysis confirmed that the α and γ isoforms of Fbxw7 interact with OASIS and BBF2H7 in vivo. Sustained overexpression of Fbxw7 resulted in marked down-regulation of OASIS and BBF2H7, whereas RNAi-mediated Fbxw7 depletion stabilized both proteins. Mutation of a putative Cdc4 phosphodegron in OASIS and BBF2H7 attenuated their association with Fbxw7 and resulted in their stabilization. Depletion of Fbxw7 promoted the differentiation of mouse C2C12 mesenchymal cells into osteoblasts in association with the accumulation of OASIS. Conversely, overexpression of Fbxw7 in C2C12 cells resulted in down-regulation of Col1A1 mRNA, a target of OASIS. Conditional ablation of Fbxw7 in primary mouse mesenchymal cells promoted chondrogenesis in association with up-regulation of BBF2H7, whereas overexpression of Fbxw7 inhibited chondrogenesis in ATDC5 cells. Collectively, our results suggest that OASIS and BBF2H7 are bona fide substrates of Fbxw7 and that Fbxw7 controls osteogenesis and chondrogenesis by targeting OASIS and BBF2H7, respectively, for degradation.

In the mammalian circadian clockwork, CRY1 and CRY2 repressor proteins are regulated by posttranslational modifications for temporally coordinated transcription of clock genes. Previous studies revealed that FBXL3, an F-box-type E3 ligase, ubiquitinates CRYs and mediates their degradation. Here, we found that FBXL21 also ubiquitinates CRYs but counteracts FBXL3. Fbxl21(-/-) mice exhibited normal periodicity of wheel-running rhythms with compromised organization of daily activities, while an extremely long-period phenotype of Fbxl3(-/-) mice was attenuated in Fbxl3/Fbxl21 double-knockout mice. The double knockout destabilized the behavioral rhythms progressively and sometimes elicited arrhythmicity. Surprisingly, FBXL21 stabilized CRYs and antagonized the destabilizing action by FBXL3. Predominantly cytosolic distribution of FBXL21 contrasts with nuclear localization of FBXL3. These results emphasize the physiological importance of antagonizing actions between FBXL21 and FBXL3 on CRYs, and their combined actions at different subcellular locations stabilize oscillation of the circadian clock., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Induced pluripotent stem cells (iPSCs) share many biological properties with embryonic stem cells (ESCs), and are generated from somatic cells by expression of some transcription factors such as Oct3/4, Sox2, Klf4 and c-Myc. Among these factors, the abundance of c-Myc is strictly regulated by Fbxw7, a subunit of Skp1-Cul1-F-box protein-type ubiquitin ligase. We have now shown that the expression of Fbxw7 was increased as ESCs differentiated. To investigate the role of Fbxw7 in the ESCs/iPSCs, we examined the impact of Fbxw7 ablation in the efficiency in iPSC generation. The frequency of iPSC generation from mouse embryonic fibroblasts (MEFs) lacking Fbxw7 was markedly greater than that from control MEFs. Depletion of Fbxw7 also resulted in promotion of iPSC generation. Morphology of iPSC clonies from Fbxw7-depleted MEFs appeared more undifferentiated than that from MEFs overexpressing c-Myc. Additional depletion of c-Myc did not abrogate the effect of Fbxw7 depletion, suggesting that c-Myc accumulation is not necessarily required for the increased efficiency in iPSC generation by Fbxw7 ablation. Substrates of Fbxw7 other than c-Myc might therefore play a key role in iPSC generation. These results suggest that transient inhibition of Fbxw7 would be a more promising approach to efficient generation of iPSCs than c-Myc over-expression., (© 2012 The Authors Journal compilation © 2012 by the Molecular Biology Society of Japan/Wiley Publishing Ltd.)

Although elucidation of enzyme-substrate relations is fundamental to the advancement of biology, universal approaches to the identification of substrates for a given enzyme have not been established. It is especially difficult to identify substrates for ubiquitin ligases, given that most such substrates are immediately ubiquitylated and degraded as a result of their association with the enzyme. We here describe the development of a new approach, DiPIUS (differential proteomics-based identification of ubiquitylation substrates), to the discovery of substrates for ubiquitin ligases. We applied DiPIUS to Fbxw7α, Skp2, and Fbxl5, three of the most well-characterized F-box proteins, and identified candidate substrates including previously known targets. DiPIUS is thus a powerful tool for unbiased and comprehensive screening for substrates of ubiquitin ligases.