Background N6-methyladenosine (m6A) is the most abundant modification in mRNA of humans. Emerging evidence has supported the fact that m6A is comprehensively involved in various diseases especially cancers. As a crucial reader, YTHDF2 usually mediates the degradation of m6A-modified mRNAs in m6A-dependent way. However, the function and mechanisms of m6A especially YTHDF2 in prostate cancer (PCa) still remain elusive. Methods To investigate the functions and mechanisms of YTHDF2 in PCa, in vitro, in vivo biofunctional assays and epigenetics experiments were performed. Endogenous expression silencing of YTHDF2 and METTL3 was established with lentivirus-based shRNA technique. Colony formation, flow cytometry and trans-well assays were performed for cell function identifications. Subcutaneous xenografts and metastatic mice models were combined with in vivo imaging system to investigate the phenotypes when knocking down YTHDF2 and METTL3. m6A RNA immunoprecipitation (MeRIP) sequencing, mRNA sequencing, RIP-RT-qPCR and bioinformatics analysis were mainly used to screen and validate the direct common targets of YTHDF2 and METTL3. In addition, TCGA database was also used to analyze the expression pattern of YTHDF2, METTL3 and the common target LHPP in PCa, and their correlation with clinical prognosis. Results The upregulated YTHDF2 and METTL3 in PCa predicted a worse overall survival rate. Knocking down YTHDF2 or METTL3 markedly inhibited the proliferation and migration of PCa in vivo and in vitro. LHPP and NKX3–1 were identified as the direct targets of both YTHDF2 and METTL3. YTHDF2 directly bound to the m6A modification sites of LHPP and NKX3–1 to mediate the mRNA degradation. Knock-down of YTHDF2 or METTL3 significantly induced the expression of LHPP and NKX3–1 at both mRNA and protein level with inhibited phosphorylated AKT. Overexpression of LHPP and NKX3–1 presented the consistent phenotypes and AKT phosphorylation inhibition with knock-down of YTHDF2 or METTL3. Phosphorylated AKT was consequently confirmed as the downstream of METTL3/YTHDF2/LHPP/NKX3–1 to induce tumor proliferation and migration. Conclusion We propose a novel regulatory mechanism in which YTHDF2 mediates the mRNA degradation of the tumor suppressors LHPP and NKX3–1 in m6A-dependent way to regulate AKT phosphorylation-induced tumor progression in prostate cancer. We hope our findings may provide new concepts of PCa biology.

This study investigated the air pollution characteristics of synoptic-scale circulation in the Beijing megacity, and provided quantitative evaluation of the impacts of circulation patterns on air quality during the 2008 Beijing Summer Olympics. Nine weather circulation types (CTs) were objectively identified over the North China region during 2000–2009, using obliquely rotated T-mode principal component analysis (PCA). The resulting CTs were examined in relation to the local meteorology, regional transport pathways, and air quality parameters, respectively. The FLEXPART-WRF model was used to calculate 48-h backward plume trajectories for each CT. Each CT was characterized with distinct local meteorology and air mass origin. CT 1 (high pressure to the west with a strong pressure gradient) was characterized by a northwestern air mass origin, with the smallest local and southeasterly air mass sources, and CT 6 (high pressure to the northwest) had air mass sources mostly from the north and east. On the contrary, CTs 5, 8, and 9 (weak pressure field, high pressure to the east, and low pressure to the northwest, respectively) were characterized by southern and southeastern trajectories, which indicated a greater influence of high pollutant emission sources. In turn, poor air quality in Beijing (high loadings of PM₁₀, BC, SO₂, NO₂, NO_x, O₃, AOD, and low visibility) was associated with these CTs. Good air quality in Beijing was associated with CTs 1 and 6. The average visibilities (with ±1&sigma;) in Beijing for CTs 1 and 6 during 2000–2009 were 18.5 ± 8.3 km and 14.3 ± 8.5 km, respectively. In contrast, low visibility values of 6.0 ± 3.5 km, 6.6 ± 3.7 km, and 6.7 ± 3.6 km were found in CTs 5, 8, and 9, respectively. The mean concentrations of PM₁₀ for CTs 1, 6, 5, 8, and 9 during 2005–2009 were 90.3 ± 76.3 μg m⁻³, 111.7 ± 89.6 μg m⁻³, 173.4 ± 105.8 μg m⁻³, 158.4 ± 90.0 μg m⁻³, and 151.2 ± 93.1 μg m⁻³, respectively. <br></br> Analysis of the relationship between circulation pattern and air quality during the emission control period suggests that CTs are the primary drivers of day-to-day variations in pollutant concentrations over Beijing and its vicinity. During the Olympics period, the frequency of CT 6 was twice that of the mean in August from 2000 to 2009. This CT had northerly transport pathways and favorable meteorological conditions (e.g. frequent precipitation) for clean air during the Olympics. Assuming that relationships between CTs and air quality parameters in the same season are fixed in different years, the relative contributions of synoptic circulation to decreases in PM₁₀, BC, SO₂, NO₂, NO_x, CO, and horizontal light extinction during the Olympics were ...

This study investigates the October and November MJO events observed during the Cooperative Indian Ocean Experiment on Intraseasonal Variability in the Year 2011 (CINDY)/Dynamics of the MJO (DYNAMO) field campaign through cloud-permitting numerical simulations. The simulations are compared to multiple observational datasets. The control simulation at 9-km horizontal grid spacing captures the slow eastward progression of both the October and November MJO events in surface precipitation, outgoing longwave radiation, zonal wind, humidity, and large-scale vertical motion. The vertical motion shows weak ascent in the leading edge of the MJO envelope, followed by deep ascent during the peak precipitation stage and trailed by a broad second baroclinic mode structure with ascent in the upper troposphere and descent in the lower troposphere. Both the simulation and the observations also show slow northward propagation components and tropical cyclone-like vortices after the passage of the MJO active phase. Comparison with synthesized observations from the northern sounding array shows that the model simulates the passage of the two MJO events over the sounding array region well. Sensitivity experiments to SST indicate that daily SST plays an important role for the November MJO event, but much less so for the October event.Analysis of the moist static energy (MSE) budget shows that both advection and diabatic processes (i.e., surface fluxes and radiation) contribute to the development of the positive MSE anomaly in the active phase, but their contributions differ by how much they lead the precipitation peak. In comparison to the observational datasets used here, the model simulation may have a stronger surface flux feedback and a weaker radiative feedback. The normalized gross moist stability in the simulations shows an increase from near-zero values to ;0.8 during the active phase, similar to what is found in the observational datasets.

| INTRODUC TI ONBladder cancer (BCa) is the most common malignant tumour of the urinary tract and the 10th most common type of carcinoma worldwide. Approximately 549 000 new cases and 200 000 deaths were estimated by GLOBOCAN in 2018. 1 In 2019, approximately 80 470 patients (including 61 700 men) were diagnosed with BCa and 17 670 patients (including 12 870 men) died from BCa in the United States; thus, BCa ranks the forth in incidence and eighth in mortality in men. 2 The increasing trend in these numbers constantly urges researchers to better understand the mechanisms underlying the pathogenesis of BCa to identify potential therapies against BCa. m 6 A, a modification first identified in mRNA-enriched RNA fractions in 1974, 3 refers to methylation of the N6 position of adenosine bases, which are widely distributed in the mammalian mRNA. 4,5 With the application of available methods for detecting m 6 A, insights into the regulatory mechanism have been revealed in recent years. m 6 A RNA modification is a dynamic and reversible posttranscriptional modification process maintained by a multicomponent Abstract N6-Methyladenosine (m 6 A) modification, the most prevalent modification of eukaryotic messenger RNA (mRNA), is involved in the progression of various tumours.However, the specific role of m 6 A in bladder cancer (BCa) is still poorly understood.In this study, we demonstrated the tumour-promoting function and specific regulatory mechanism of m 6 A axis, consisting of the core 'writer' protein METTL3 and the major reader protein YTHDF2. Depletion of METTL3 impaired cancer proliferation and cancer metastasis in vitro and in vivo. Through transcriptome sequencing, m 6 A methylated RNA immunoprecipitation (MeRIP) and RIP, we determined that the METTL3/YTHDF2 m 6 A axis directly degraded the mRNAs of the tumour suppressors SETD7 and KLF4, contributing to the progression of BCa. In addition, overexpression of SETD7 and KLF4 revealed a phenotype consistent with that induced by depletion of the m 6 A axis. Thus, our findings on the METTL3/YTHDF2/SETD7/KLF4 m 6 A axis provide the insight into the underlying mechanism of carcinogenesis and highlight potential therapeutic targets for BCa. K E Y W O R D Sbladder cancer, carcinogenesis, METTL3/YTHDF2 m 6 A axis, mRNA degradation, RNA modification | 4093 XIE Et al.

As the most abundant and reversible RNA modification in eukaryotic cells, m6A triggers a new layer of epi‐transcription. M6A modification occurs through a methylation process modified by “writers” complexes, reversed by “erasers”, and exerts its role depending on various “readers”. Emerging evidence shows that there is a strong association between m6A and human diseases, especially cancers. Herein, we review bi‐aspects of m6A in regulating cancers mediated by the m6A‐associated proteins, which exert vital and specific roles in the development of various cancers. Generally, the m6A modification performs promotion or inhibition functions (dual role) in tumorigenesis and progression of various cancers, which suggests a new concept in cancer regulations. In addition, m6A‐targeted therapies including competitive antagonists of m6A‐associated proteins may provide a new tumour intervention in the future.